Novel benzimidazole compound and medical use thereof

ABSTRACT

The present invention provides a medicament for treating a disease involving Nav 1.7 such as neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, and multiple sclerosis, which comprises a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 1c  and R 1d  are hydrogen, halogen, cyano, C 1-4  alkyl, C 1-4  alkoxy, or the like, provided that at least one of R 1a , R 1b , R 1c  and R 1d  is C 6-10  aryl, C 6-10  aryloxy, or the like, R 2  and R 3  are hydrogen, C 1-6  alkyl, C 3-10  cycloalkyl, or the like, R 4  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, or the like, m is 1, 2 or 3, L is CR 7 R 8 , and R 7  and R 8  are hydrogen, hydroxyl, C 1-4  alkyl, C 1-4  alkoxy, or the like.

TECHNICAL FIELD

The present invention may relate to a medicament for treating orpreventing a disease involving Na channel, particularly SCN9A (Nav 1.7),which comprises a novel compound having a benzimidazole skeleton or apharmaceutically-acceptable salt thereof as an active ingredient. Inmore detail, it relates to a medicament for treating or preventing adisease such as neuropathic pain, nociceptive pain, inflammatory pain,small-fiber neuropathy, erythromelalgia, paroxysmal extreme paindisorder, dysuria, and multiple sclerosis.

BACKGROUND ART

Voltage-dependent Na channel a subunit that forms pore is known toinclude 9 kinds at present. Recently, it has been evidenced that thesubunit, particularly Nav 1.7 is broadly concerned in the signaltransduction of acute and chronic pain.

SCN9A (Nav 1.7) is tetrodotoxin (TTX)-sensitive Na channel localized inthe peripheral sensory nerve or sympathetic nerve, which is alsoreferred to as NENA or PN1. Physiologically, Nav 1.7 channel functionsto amplify a pain signal (i.e., generate a generator potential) at thesensory nerve ending. In the field of genetic investigation, it has beengetting evident that a human whose SCN9A gene mutates to result inloss-of-function shows congenital insensitivity to pain. Reversely, inpatients suffering from a severe orphan disease such as erythromelalgiaand paroxysmal extreme pain disorder, it is observed that SCN9A genemutates to result in gain-of-function. Furthermore, it has been reportedthat approximately 30% of patients suffering from small fiber neuropathyhave genetic polymorphism to enhance Nav 1.7 function (Non-PatentLiterature 1). And, it is suggested that Nav 1.7 channel function isdirectly concerned in the hyperexcitability of DRG neuron in patientssuffering from pain since the expression level and activity increase inDRG neuron of model animals suffering from chronic pain, and neuropathicpain and inflammatory pain decrease in a knockout experiment (Non-PatentLiterature 2).

Patent Literature 1 discloses a benzimidazole derivative represented bythe following formula (A), but the compound have2-((4-cyclopropylpyridin-2-yl)amino)isonicotinonitrile as an essentialpartial structure, which is different from the compound of the presentinvention. And, the invention described in Patent Literature 1 isdirected to a Syk tyrosine kinase inhibitor, thus Patent Literature 1does not disclose the present invention at all.

CITATION LIST Patent Literature

-   [Patent Literature 1] WO 2012/057262

Non-Patent Literature

-   [Non-Patent Literature 1] Nat Rev Neurosci. 14: 49, 2013-   [Non-Patent Literature 2] Nat Commun. 3: 791, 2012

SUMMARY OF INVENTION Technical Problem

The purpose of the present invention may be to provide a medicament fortreating or preventing a disease involving Nav 1.7, specifically such asneuropathic pain, nociceptive pain, inflammatory pain, small-fiberneuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria,and multiple sclerosis.

Solution to Problem

The present inventors have conducted intensive studies in an attempt tosolve the aforementioned problem and found that a compound having abenzimidazole ring mentioned below or a pharmaceutically acceptable saltthereof can inhibit the membrane potential change or the Na ion currentitself via Na channel in Nav 1.7 gene expressing cell, i.e., thecompound or a pharmaceutically acceptable salt thereof is a blockerhaving a inhibitory activity for Nav 1.7. In addition, the presentinventors have found that the derivative is useful as a medicament fortreating or preventing a disease such as neuropathic pain, nociceptivepain, inflammatory pain, small-fiber neuropathy, erythromelalgia, andparoxysmal extreme pain disorder, which resulted in the completion ofthe present invention. Accordingly, the present invention can provide abenzimidazole compound represented by the following formula (I)(hereinafter, also referred to as “compound represented by formula (I)”or “compound of formula (I)”) or a pharmaceutically acceptable saltthereof (hereinafter, also referred to as “compound of the presentinvention”).

The present invention can show as follows.

Term 1

A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R^(1a), R^(1b), R^(1c), and R^(1d) are independently hydrogen, halogen,cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, (wherein each alkylmoiety of the alkyl, the alkoxy and the alkylamino may be independentlysubstituted with 1 to 5 substituents selected independently from thegroup consisting of halogen, hydroxyl, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₃₋₇ cycloalkyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, C₃₋₇cycloalkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, and 3- to 7-memberednon-aromatic heterocyclyl optionally-substituted with 1 to 3substituents selected independently from Substituent-group B), C₃₋₇cycloalkyl, C₃₋₇ cycloalkoxy, C₃₋₇ cycloalkylamino, (wherein eachcycloalkyl moiety of the cycloalkyl, the cycloalkoxy and thecycloalkylamino may be independently substituted with 1 to substituentsselected independently from the group consisting of halogen, hydroxyl,C₁₋₄ alkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₃₋₇ cycloalkyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, andC₃₋₇ cycloalkoxy optionally-substituted with 1 to 3 substituentsselected independently from Substituent-group B), C₆₋₁₀ aryl, C₆₋₁₀aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-memberedheteroaryloxy, (wherein each aryl moiety of the aryl and the aryloxy andeach heteroaryl moiety of the heteroaryl and the heteroaryloxy may beindependently substituted with 1 to 5 substituents selectedindependently from the group consisting of halogen, cyano, C₁₋₄ alkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₁₋₄ alkylthio optionally-substituted with 1to 3 substituents selected independently from Substituent-group A, andC₁₋₄ alkylsulfonyl optionally-substituted with 1 to 3 substituentsselected independently from Substituent-group A), provided that at leastone of R^(1a), R^(1b), R^(1c) and R^(1d) is the above C₆₋₁₀ aryl, C₆₋₁₀aryloxy, 5- to 12-membered heteroaryl or 5- to 12-memberedheteroaryloxy,

R² and R³ are independently hydrogen, C₁₋₆ alkyl which may beindependently substituted with 1 to 5 substituents selectedindependently from the group consisting of cyano, halogen, hydroxyl,C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB, or C₃₋₁₀ cycloalkyl,

R⁴ is hydrogen, C₁₋₆ alkyl which may be substituted with 1 to 3substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, or C₃₋₇ cycloalkyl which may be independentlysubstituted with 1 to 3 substituents selected independently from thegroup consisting of halogen, hydroxyl, C₁₋₄ alkyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA, C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB,

m is 1, 2 or 3,

L is CR⁷R⁸ provided that when m is 2 or 3, each CR⁷R⁸ are independentlythe same or different,

R⁷ and R⁸ are independently hydrogen, hydroxyl, C₁₋₄ alkyl, C₁₋₄ alkoxy,(wherein each alkyl moiety of the alkyl and the alkoxy may beindependently substituted with 1 to 3 substituents selectedindependently from the group consisting of halogen, hydroxyl, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₃₋₇ cycloalkoxy optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, and3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B), C₃₋₇cycloalkyl, or C₃₋₇ cycloalkoxy, (wherein each cycloalkyl moiety of thecycloalkyl and the cycloalkoxy may be independently substituted with 1to 3 substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkyl optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB), or

in R², R³ and —OR⁴, R² and R³ may be combined together with the carbonatom to which they are attached to form the following group of formula(II) with —OR⁴

in formula (II),

e and f are independently 1, 2 or 3,

R⁴ is as defined above,

V is single bond or oxygen atom,

R^(5a), R^(5b), R^(5c), and R^(5d) are independently hydrogen, halogen,hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy, wherein each alkyl moiety of thealkyl and the alkoxy may be independently substituted with 1 to 3substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, or

in R², R³, —OR⁴ and CR⁷R⁸ in L,

R² and R⁷ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IV) with R³, —OR⁴and R⁸

in formula (IV),

m¹ is 0 or 1,

m² is 0 or 1 and j is 1, 2, 3 or 4 when m¹ is 1, or

m² is 0, 1 or 2 and j is 1, 2, 3 or 4 when m¹ is 0,

R³, R⁴, R⁸ and L are as defined above,

R^(9a), R^(9b), R^(9c), and R^(9d) are independently hydrogen, halogen,hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy, wherein each alkyl moiety of thealkyl and the alkoxy may be independently substituted with 1 to 3substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, or

R³ and —OR⁴ may be combined together with the carbon atom to which theyare attached to form the following group of formula (III) with R²

in formula (III),

h is 1, 2, 3, or 4,

R² is as defined above,

R^(6a), R^(6b), and R^(6c) are independently hydrogen, halogen,hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy, wherein each alkyl moiety of thealkyl and the alkoxy may be independently substituted with 1 to 3substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B,

provided that all of R², R³ and —OR⁴ are not combined together to form aring,

Substituent-group A is independently halogen, hydroxyl, C₁₋₄ alkoxy,C₃₋₇ cycloalkyl, or C₃₋₇ cycloalkoxy, and

Substituent-group B is independently halogen, hydroxyl, C₁₋₄ alkyl, C₁₋₄alkoxy, C₃₋₇ cycloalkyl, or C₃₋₇ cycloalkoxy,

provide that the following compounds are excluded:

-   6-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-1-(2-methoxyethyl)-1H-benzimidazole,-   2-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-1-yl]ethanol,-   2-{5-[5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl]-1H-benzimidazol-1-yl}ethanol,-   2-{5-[3-(2-methoxyethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol,-   2-{5-[3-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol,-   2-butyl-6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,-   6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-2-(3-methylbutyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,-   2-{5-[1-(2-hydroxyethyl)-1H-benzimidazol-5-yl]-1H-1,2,4-triazol-1-yl}ethanol,-   6-(2-chlorophenyl)-1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile,-   2-chloro-6-{7-fluoro-1-[(1S,3S)-3-methoxycyclohexyl]-1H-benzimidazol-5-yl}-9-(tetrahydro-2H-pyran-2-yl)-9H-purine,    and-   2-{5-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]-1H-benzimidazol-1-yl}ethanol.

Term 2

The compound of Term 1 presented in formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R^(1a), R^(1b), R^(1c), and R^(1d) are independently hydrogen, halogen,cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, (wherein each alkylmoiety of the alkyl, the alkoxy and the alkylamino may be independentlysubstituted with 1 to 5 substituents selected independently from thegroup consisting of halogen, hydroxyl, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₃₋₇ cycloalkyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, C₃₋₇cycloalkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, and 3- to 7-memberednon-aromatic heterocyclyl optionally-substituted with 1 to 3substituents selected independently from Substituent-group B), C₃₋₇cycloalkyl, C₃₋₇ cycloalkoxy, C₃₋₇ cycloalkylamino, (wherein eachcycloalkyl moiety of the cycloalkyl, the cycloalkoxy and thecycloalkylamino may be independently substituted with 1 to substituentsselected independently from the group consisting of halogen, hydroxyl,C₁₋₄ alkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₃₋₇ cycloalkyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, andC₃₋₇ cycloalkoxy optionally-substituted with 1 to 3 substituentsselected independently from Substituent-group B), C₆₋₁₀ aryl, C₆₋₁₀aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-memberedheteroaryloxy, (wherein each aryl moiety of the aryl and the aryloxy andeach heteroaryl moiety of the heteroaryl and the heteroaryloxy may beindependently substituted with 1 to 5 substituents selectedindependently from the group consisting of halogen, cyano, C₁₋₄ alkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₁₋₄ alkylthio optionally-substituted with 1to 3 substituents selected independently from Substituent-group A, andC₁₋₄ alkylsulfonyl optionally-substituted with 1 to 3 substituentsselected independently from Substituent-group A), provided that at leastone of R^(1a), R^(1b), R^(1c) and R^(1d) is the above C₆₋₁₀ aryl, C₆₋₁₀aryloxy, 5- to 12-membered heteroaryl or 5- to 12-memberedheteroaryloxy,

R² and R³ are independently hydrogen, C₁₋₆ alkyl which may beindependently substituted with 1 to 5 substituents selectedindependently from the group consisting of cyano, halogen, hydroxyl,C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB, or C₃₋₁₀ cycloalkyl,

R⁴ is hydrogen, C₁₋₆ alkyl which may be independently substituted with 1to 3 substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, or C₃₋₇ cycloalkyl which may be independentlysubstituted with 1 to 3 substituents selected independently from thegroup consisting of halogen, hydroxyl, C₁₋₄ alkyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA, C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB,

m is 1, 2 or 3,

L is CR⁷R⁸ provided that when m is 2 or 3, each CR⁷R⁸ are independentlythe same or different,

R⁷ and R⁸ are independently hydrogen, hydroxyl, C₁₋₄ alkyl, C₁₋₄ alkoxy,(wherein each alkyl moiety of the alkyl and the alkoxy may beindependently substituted with 1 to 3 substituents selectedindependently from the group consisting of halogen, hydroxyl, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₃₋₇ cycloalkoxy optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, and3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B), C₃₋₇cycloalkyl, or C₃₋₇ cycloalkoxy, (wherein each cycloalkyl moiety of thecycloalkyl and the cycloalkoxy may be independently substituted with 1to 3 substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkyl optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB), or

in R², R³ and —OR⁴, R² and R³ may be combined together with the carbonatom to which they are attached to form the following group of formula(II) with —OR⁴

in formula (II),

e and f are independently 1, 2 or 3,

R⁴ is as defined above,

V is single bond or oxygen atom,

R^(5a), R^(5b), R^(5c), and R^(5d) are independently hydrogen, halogen,hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy, wherein each alkyl moiety of thealkyl and the alkoxy may be independently substituted with 1 to 3substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, or

R³ and —OR⁴ may be combined together with the carbon atom to which theyare attached to form the following group of formula (III) with R²

in formula (III),

h is 1, 2, 3, or 4,

R² is as defined above,

R⁶, R^(6b), and R^(6c) are independently hydrogen, halogen, hydroxyl,C₁₋₄ alkyl, or C₁₋₄ alkoxy, wherein each alkyl moiety of the alkyl andthe alkoxy may be independently substituted with 1 to 3 substituentsselected independently from the group consisting of halogen, hydroxyl,C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₃₋₇ cycloalkoxy optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, and3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B,

provided that all of R², R³ and —OR⁴ are not combined together to form aring,

Substituent-group A is independently halogen, hydroxyl, C₁₋₄ alkoxy,C₃₋₇ cycloalkyl, or C₃₋₇ cycloalkoxy, and

Substituent-group B is independently halogen, hydroxyl, C₁₋₄ alkyl, C₁₋₄alkoxy, C₃₋₇ cycloalkyl, or C₃₋₇ cycloalkoxy.

Term 3

The compound of Term 1 or 2 or a pharmaceutically acceptable saltthereof, wherein

R^(1a), R^(1b), R^(1c), and R^(1d) are independently, hydrogen, halogen,cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy (wherein each alkyl moiety of the alkyland the alkoxy may be independently substituted with the same ordifferent and 1 to 3 halogens), C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to12-membered heteroaryl, or 5- to 12-membered heteroaryloxy (wherein eacharyl moiety of the aryl and the aryloxy and each heteroaryl moiety ofthe heteroaryl and the heteroaryloxy may be independently substitutedwith 1 to 3 substituents selected independently from the groupconsisting of halogen, cyano, C₁₋₄ alkyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group A, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, and C₁₋₄ alkylsulfonyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A).

Term 4

The compound of any one of Terms 1 to 3 or a pharmaceutically acceptablesalt thereof, wherein

R^(1a), R^(1b), R^(1c), and R^(1d) are independently, hydrogen, C₆₋₁₀aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-memberedheteroaryloxy, wherein each aryl moiety of the aryl and the aryloxy andeach heteroaryl moiety of the heteroaryl and the heteroaryloxy may beindependently substituted with 1 to 3 substituents selectedindependently from the group consisting of halogen and C₁₋₄ alkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A.

Term 5

The compound of any one of Terms 1 to 4 or a pharmaceutically acceptablesalt thereof, wherein R^(1a) and R^(1d) are hydrogen.

Term 6

The compound of any one of Terms 1 and 3 to 5 or a pharmaceuticallyacceptable salt thereof, wherein

R² and R³ are independently hydrogen or C₁₋₆ alkyl which may beindependently substituted with 1 to 5 substituents selectedindependently from the group consisting of cyano, halogen, hydroxyl, andC₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, provided that both of R² and R³are not hydrogen, or

R² and R³ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIa) with —OR⁴

in formula (IIa),

e and f are independently 1 or 2,

R⁴ and V are as defined in Term 1, and

R^(5a), R^(5b), R^(5c), and R^(5d) are independently hydrogen orhalogen, or

in R², R³, —OR⁴ and CR⁷R⁸ in L,

R² and R⁷ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IVa) with R³, —OR⁴and R⁸

in formula (IVa),

m¹ is 0,

m² is 1 or 2,

j is 1, 2 or 3,

R³ is as defined above,

R⁴, R⁸ and L are as defined in Term 1, and

R^(9a), R^(9b), R^(9c), and R^(9d) are independently hydrogen orhalogen.

Term 7

The compound of any one of Terms 1 and 3 to 6 or a pharmaceuticallyacceptable salt thereof, wherein

R² and R³ are independently C₁₋₆ alkyl optionally-substituted with thesame or different and 1 to 5 halogens, or

R² and R³ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIb) with —OR⁴

in formula (IIb),

e and f are independently 1 or 2,

R⁴ and V are as defined in Term 1, and

R^(5a), R^(5b), R^(5c), and R^(5d) are independently hydrogen orhalogen, or

in R², R³, —OR⁴ and CR⁷R⁸ in L,

R² and R⁷ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IVa) with R³, —OR⁴and R⁸

in formula (IVa),

m¹ is 0,

m² is 1 or 2,

j is 1, 2 or 3,

R⁴ is hydrogen,

R⁸ and L are as defined in Term 1, and

R^(9a), R^(9b), R^(9c), and R^(9d) are independently hydrogen orhalogen.

Term 8

The compound of any one of Terms 1 to 6 or a pharmaceutically acceptablesalt thereof, wherein

R² and R³ are independently hydrogen or C₁₋₆ alkyl which may beindependently substituted with 1 to 5 substituents selectedindependently from the group consisting of cyano, halogen, hydroxyl, andC₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, or

R² and R³ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIa) with —OR⁴

in formula (IIa),

e and f are independently 1 or 2,

R⁴ and V are as defined in Term 1, and

R^(5a), R^(5b), R^(5c), and R^(5d) are independently hydrogen orhalogen.

Term 9

The compound of any one of Terms 1 to 6 or a pharmaceutically acceptablesalt thereof, wherein

R² and R³ are independently hydrogen or C₁₋₆ alkyloptionally-substituted with the same or different and 1 to 5 halogens,or

R² and R³ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIb) with —OR⁴

in formula (IIb),

e and f are independently 1 or 2,

R⁴ and V are as defined in Term 1, and

R^(5a), R^(5b), R^(5c), and R^(5d) are independently hydrogen orhalogen.

Term 10

The compound of any one of Terms 1 to 9 or a pharmaceutically acceptablesalt thereof, wherein

R² and R³ are independently hydrogen or C₁₋₆ alkyloptionally-substituted with the same or different and 1 to 5 halogens,and R² and R³ are not combined together with the carbon atom to whichthey are attached to form a ring.

Term 11

The compound of any one of Terms 1 to 5 and 10 or a pharmaceuticallyacceptable salt thereof, wherein

R⁴ is hydrogen, C₁₋₄ alkyl optionally-substituted with the same ordifferent and 1 to 3 halogens, or C₃₋₇ cycloalkyl which may besubstituted with 1 to 3 substituents selected independently from thegroup consisting of halogen, hydroxyl, and C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, or

R³ and —OR⁴ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIIa) with R²

in formula (IIIa),

h is 1, 2, or 3,

R² is as defined in Term 1,

R^(6a), R^(6b), and R^(6c) are independently, hydrogen, halogen, or C₁₋₄alkyl optionally-substituted with the same or different and 1 to 3halogens.

Term 12

The compound of any one of Terms 1 to 11 or a pharmaceuticallyacceptable salt thereof, wherein

R⁴ is hydrogen, C₁₋₄ alkyl optionally-substituted with the same ordifferent and 1 to 3 halogens, or C₃₋₇ cycloalkyl which may besubstituted with 1 to 3 substituents selected independently from thegroup consisting of halogen, hydroxyl, and C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, and R³ and —OR⁴ are not combined together withthe carbon atom to which they are attached to form a ring.

Term 13

The compound of any one of Terms 1 to 12 or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is hydrogen.

Term 14

The compound of any one of Terms 1 to 13 or a pharmaceuticallyacceptable salt thereof, wherein

R⁷ and R⁸ are independently hydrogen or C₁₋₄ alkyl which may besubstituted with 1 to 3 substituents selected independently from thegroup consisting of halogen, hydroxyl, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₃₋₇ cycloalkyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, C₃₋₇cycloalkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, and 3- to 7-memberednon-aromatic heterocyclyl optionally-substituted with 1 to 3substituents selected independently from Substituent-group B, and

m is 1 or 2.

Term 15

The compound of any one of Terms 1 to 14 or a pharmaceuticallyacceptable salt thereof, wherein R⁷ and R⁸ are hydrogen, and m is 1.

Term 16

The compound of any one of Terms 1 to 15 or a pharmaceuticallyacceptable salt thereof, wherein

R^(1b) or R^(1c) is C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-memberedheteroaryl, or 5- to 12-membered heteroaryloxy, wherein each aryl moietyof the aryl and the aryloxy and each heteroaryl moiety of the heteroaryland the heteroaryloxy may be independently substituted with 1 to 3substituents selected independently from the group consisting ofhalogen, cyano, C₁₋₄ alkyl optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, and C₁₋₄ alkylsulfonyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A.

Term 17

The compound of any one of Terms 1 to 16 or a pharmaceuticallyacceptable salt thereof, wherein

R^(1b) is C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl, or 5-to 12-membered heteroaryloxy, wherein each aryl moiety of the aryl andthe aryloxy and each heteroaryl moiety of the heteroaryl and theheteroaryloxy may be independently substituted with 1 to 3 substituentsselected independently from the group consisting of halogen, cyano, C₁₋₄alkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, and C₁₋₄ alkylsulfonyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA.

Term 18

The compound of any one of Terms 1 to 16 or a pharmaceuticallyacceptable salt thereof, wherein

R^(1c) is C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl, or 5-to 12-membered heteroaryloxy, wherein each aryl moiety of the aryl andthe aryloxy and each heteroaryl moiety of the heteroaryl and theheteroaryloxy may be independently substituted with 1 to 3 substituentsselected independently from the group consisting of halogen, cyano, C₁₋₄alkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, and C₁₋₄ alkylsulfonyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA.

Term 19

The compound of any one of Terms 1 to 16 or a pharmaceuticallyacceptable salt thereof, wherein

R^(1b) or R^(1c) is C₆₋₁₀ aryloxy or 5- to 12-membered heteroaryloxywherein the aryl moiety of the aryloxy and the heteroaryl moiety of theheteroaryloxy may be independently substituted with 1 to 3 substituentsselected independently from the group consisting of halogen, cyano, C₁₋₄alkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, and C₁₋₄ alkylsulfonyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA.

Term 20

The compound of any one of Terms 1 to 16 or a pharmaceuticallyacceptable salt thereof, wherein

R^(1b) or R^(1c) is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl whereinthe aryl and the heteroaryl may be independently substituted with 1 to 3substituents selected independently from the group consisting ofhalogen, cyano, C₁₋₄ alkyl optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, and C₁₋₄ alkylsulfonyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A.

Term 21

The compound of any one of Terms 1 to 20 or a pharmaceuticallyacceptable salt thereof, wherein R² and R³ are independently C₁₋₆ alkyloptionally-substituted with the same or different and 1 to 5 halogens.

Term 22

The compound of any one of Terms 1 and 3 to 20 or a pharmaceuticallyacceptable salt thereof, wherein

R² and R³ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIb) with —OR⁴

in formula (IIb),

e and f are independently 1 or 2,

R⁴ and V are as defined in Term 1, and

R^(5a), R^(5b), R^(5c), and R^(5d) are independently hydrogen orhalogen, or

in R², R³, —OR⁴ and CR⁷R⁸ in L,

R² and R⁷ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IVa) with R³, —OR⁴and R⁸

in formula (IVa),

m¹ is 0,

m² is 1 or 2,

j is 1, 2 or 3,

R⁴ is hydrogen,

R⁸ and L are as defined in Term 1, and

R^(9a), R^(9b), R^(9c), and R^(9d) are independently hydrogen orhalogen.

Term 23

The compound of Term 1 or 2, or a pharmaceutically acceptable saltthereof, which is selected from the following compounds:

-   Example 1:    1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,-   Example 2:    6-(4-fluorophenoxy)-1-(tetrahydrofuran-2-ylmethyl)-1H-benzimidazole,-   Example 7:    1-(tetrahydrofuran-2-ylmethyl)-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,-   Example 9:    2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 10:    1-[2-(cyclopentyloxy)ethyl]-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,-   Example 11:    2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 12:    1-[2-(cyclopentyloxy)ethyl]-6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazole,-   Example 14:    2-methyl-1-[6-(4-methylphenoxy)-1H-benzimidazol-1-yl]propan-2-ol,-   Example 15:    2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 20:    1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,-   Example 22:    2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 24:    2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 25:    2-methyl-1-(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 28:    2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 51:    2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 52:    2-methyl-1-(5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 53:    1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,-   Example 54:    1-{5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,-   Example 56:    3-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]oxetan-3-ol,-   Example 58:    1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]cyclobutanol,-   Example 59:    2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol,-   Example 60:    2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 93:    3-({6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,-   Example 94:    3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,-   Example 101:    4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol,-   Example 110:    3-{[6-(2-chloro-4-fluorophenoxy)-1H-benzimidazol-1-yl]methyl}oxetan-3-ol,-   Example 118:    cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol,-   Example 123:    1-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,-   Example 130:    1-[6-(4-chloro-2-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,-   Example 148:    3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,-   Example 173:    4-{6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylbutan-2-ol,-   Example 176:    1-{5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,-   Example 179:    2-methyl-1-{5-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 181:    1-{5-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,-   Example 205:    3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,    and-   Example 229:    (3S)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol.

Term 24

The compound of Term 1 or 2, or a pharmaceutically acceptable saltthereof, which is selected from the following compounds:

-   Example 1:    1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,-   Example 2:    6-(4-fluorophenoxy)-1-(tetrahydrofuran-2-ylmethyl)-1H-benzimidazole,-   Example 7:    1-(tetrahydrofuran-2-ylmethyl)-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,-   Example 9:    2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 10:    1-[2-(cyclopentyloxy)ethyl]-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,-   Example 11:    2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 12:    1-[2-(cyclopentyloxy)ethyl]-6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazole,-   Example 14:    2-methyl-1-[6-(4-methylphenoxy)-1H-benzimidazol-1-yl]propan-2-ol,-   Example 15:    2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 20:    1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,-   Example 22:    2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 24:    2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 25:    2-methyl-1-(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 28:    2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 51:    2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 52:    2-methyl-1-(5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 53:    1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,-   Example 54:    1-{5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,-   Example 56:    3-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]oxetan-3-ol,-   Example 58:    1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]cyclobutanol,-   Example 59:    2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol,    and-   Example 60:    2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol.

Term 25

The compound of Term 1 or 2, or a pharmaceutically acceptable saltthereof, which is selected from the following compounds:

-   Example 1:    1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,-   Example 9:    2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 11:    2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 15:    2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 20:    1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,-   Example 22:    2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 24:    2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 28:    2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 51:    2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 53:    1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,-   Example 59:    2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol,-   Example 60:    2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 94:    3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,-   Example 101:    4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol,-   Example 118:    cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol,-   Example 123:    l-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,-   Example 148:    3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,-   Example 205:    3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,    and-   Example 229:    (3S)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol.

Term 26

The compound of Term 1 or 2, or a pharmaceutically acceptable saltthereof, which is selected from the following compounds:

-   Example 1:    1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,-   Example 9:    2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 11:    2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 15:    2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 20:    1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,-   Example 22:    2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 24:    2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,-   Example 28:    2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 51:    2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,-   Example 53:    1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,-   Example 59:    2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol,    and-   Example 60:    2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol.

Term 27

A pharmaceutical composition comprising the compound of any one of Terms1 to 26 or a pharmaceutically acceptable salt thereof.

Term 28

A medicament for treating a disease involving Nav 1.7 (SCN9A),comprising the compound of any one of Terms 1 to 26 or apharmaceutically acceptable salt thereof as an active ingredient.

Term 29

A compound of any one of Terms 1 to 26 or a pharmaceutically acceptablesalt thereof, or a compound selected from the group consisting of

-   6-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-1-(2-methoxyethyl)-1H-benzimidazole,-   2-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-1-yl]ethanol,-   2-{5-[5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl]-1H-benzimidazol-1-yl}ethanol,-   2-{5-[3-(2-methoxyethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol,-   2-{5-[3-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol,-   2-butyl-6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,-   6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-2-(3-methylbutyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,-   2-{5-[1-(2-hydroxyethyl)-1H-benzimidazol-5-yl]-1H-1,2,4-triazol-1-yl}ethanol,-   6-(2-chlorophenyl)-1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile,-   2-chloro-6-{7-fluoro-1-[(1S,3S)-3-methoxycyclohexyl]-1H-benzimidazol-5-yl}-9-(tetrahydro-2H-pyran-2-yl)-9H-purine,    and-   2-{5-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]-1H-benzimidazol-1-yl}ethanol,    or a pharmaceutically acceptable salt thereof.

Term 30

A medicament for treating a disease involving Nav 1.7 (SCN9A),comprising the compound of Term 29 or a pharmaceutically acceptable saltthereof as an active ingredient.

Term 29 is the same as any one of Terms 1 to 26, provided that the 11compounds excluded at the proviso in the end of Term 1 should not beexcluded.

Term 31

A medicament for treating neuropathic pain, nociceptive pain,inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmalextreme pain disorder, dysuria, or multiple sclerosis, which comprisesthe compound of any one of Terms 1 to 26 or a pharmaceuticallyacceptable salt thereof as an active ingredient.

Term 32

A medicament for treating neuropathic pain, nociceptive pain,inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmalextreme pain disorder, dysuria, or multiple sclerosis, which comprisesthe compound of Term 29 or a pharmaceutically acceptable salt thereof asan active ingredient.

Term 33

A pharmaceutical combination comprising the compound of any one of Terms1 to 26 or a pharmaceutically acceptable salt thereof, and at least onedrug selected from the group consisting of an antiepileptic agent, anantidepressive agent, a narcotic analgesic, an anti-inflammatory agent,a reductase inhibitor, and a prostaglandin derivative drug.

Term 34

A pharmaceutical combination comprising the compound of Term 29 or apharmaceutically acceptable salt thereof, and at least one drug selectedfrom the group consisting of an antiepileptic agent, an antidepressiveagent, a narcotic analgesic, an anti-inflammatory agent, a reductaseinhibitor, and a prostaglandin derivative drug.

Term 35

Use of the compound of any one of Terms 1 to 26 or a pharmaceuticallyacceptable salt thereof in the manufacture of a medicament for treatingneuropathic pain, nociceptive pain, inflammatory pain, small-fiberneuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria,or multiple sclerosis.

Term 36

Use of the compound of Term 29 or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for treating neuropathicpain, nociceptive pain, inflammatory pain, small-fiber neuropathy,erythromelalgia, paroxysmal extreme pain disorder, dysuria, or multiplesclerosis.

Term 37

A method for treating neuropathic pain, nociceptive pain, inflammatorypain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme paindisorder, dysuria, or multiple sclerosis, which comprises administeringa therapeutically effective amount of the compound of any one of Terms 1to 26 or a pharmaceutically acceptable salt thereof to a mammal in needthereof.

Term 38

A method for treating neuropathic pain, nociceptive pain, inflammatorypain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme paindisorder, dysuria, or multiple sclerosis, which comprises administeringa therapeutically effective amount of the compound of Term 29 or apharmaceutically acceptable salt thereof to a mammal in need thereof.

Effect of Invention

The present invention provides a Nav 1.7 blocker comprising a novelbenzimidazole compound or a pharmaceutically acceptable salt thereof.The compounds of the present invention are useful as a medicament fortreating or preventing a disease involving Nav 1.7 (SCN9A), namely, thecompounds are applicable to a patient suffering from neuropathic pain,nociceptive pain, inflammatory pain, small-fiber neuropathy,erythromelalgia, paroxysmal extreme pain disorder, and the like.

DESCRIPTION OF EMBODIMENTS

Hereafter, the present invention is explained in more detail. The numberof carbon atoms in the “substituent group” used herein can be sometimesexpressed, for example, as “C₁₋₆”. Specifically, the term “C₁₋₆ alkyl”means an alkyl having 1 to 6 carbon atoms. In the present description, asubstituent group which is not accompanied with “optionally-substituted”or “substituted” means an “unsubstituted” substituent group. Forexample, “C₁₋₆ alkyl” means “unsubstituted C₁₋₆ alkyl”.

The substituent groups in the present description may be sometimesexpressed without the term “group”. In case that“optionally-substituted” is used in the definition of substituentgroups, the number of the substituting groups is not limited as long asthe substitutions are available, i.e., it is one or more. It means thatthe possible number of substituting groups is the substitution-availablenumber on carbon atoms or carbon-nitrogen atoms in a substituent groupwhich are acceptable for substitution. Unless otherwise specified, thedefinition of each substituent group also extends over the case ofpartially-including the substituent group or the case that thesubstituent group substituting another substituent groups.

Unless otherwise specified, the binding site of substituent groups isnot limited as long as the site is available to be bound.

The “halogen” includes, for example, fluorine, chlorine, bromine, andiodine, preferably fluorine and chlorine.

The “C₁₋₂ alkyl” means a saturated hydrocarbon group having 1 to 2carbon atoms, the “C₁₋₃ alkyl” means a saturated straight or branchedchain hydrocarbon group having 1 to 3 carbon atoms, the “C₁₋₄ alkyl”means a saturated straight or branched chain hydrocarbon group having 1to 4 carbon atoms, and the “C₁₋₆ alkyl” means a saturated straight orbranched chain hydrocarbon group having 1 to 6 carbon atoms. The “C₁₋₂alkyl” includes, for example, methyl and ethyl; the “C₁₋₃ alkyl”includes, for example, propyl and isopropyl, besides the above alkyl;the “C₁₋₄ alkyl” includes, for example, butyl, isobutyl, sec-butyl, andtert-butyl, besides the above alkyl; and the “C₁₋₆ alkyl” includes, forexample, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, and astructural isomer thereof, besides the above alkyl. Preferred examplesof the “C₁₋₆ alkyl” or “C₁₋₄ alkyl” include “C₁₋₃ alkyl”, and morepreferably methyl and ethyl.

The “C₃₋₇ cycloalkyl” means a non-aromatic cyclic hydrocarbon group(i.e., saturated hydrocarbon group and partially-unsaturated hydrocarbongroup) having 3 to 7 carbon atoms, and the “C₃₋₁₀ cycloalkyl” means anon-aromatic cyclic hydrocarbon group (i.e., saturated hydrocarbon groupand partially-unsaturated hydrocarbon group) having 3 to 10 carbonatoms. The “C₃₋₇ cycloalkyl” and the “C₃₋₁₀ cycloalkyl” also include abridged one. The “C₃₋₇ cycloalkyl” includes, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, andcycloheptyl. The “C₃₋₁₀ cycloalkyl” includes, for example, cyclooctyland adamantyl, besides the above, preferably, “C₃₋₇ cycloalkyl”.

The “C₃₋₇ cycloalkyl” and the “C₃₋₁₀ cycloalkyl” also include abi-cyclic condensed ring in which the “C₃₋₇ cycloalkyl” and “C₃₋₁₀cycloalkyl” are fused with benzene or a 5- or 6-membered ring having oneheteroatom selected from nitrogen, sulfur, or oxygen atom, or the sameor different and two or more (for example, 2 to 4) heteroatoms thereof(for example, “5- or 6-membered mono-cyclic heteroaryl” mentioned below,and 5- or 6-membered ring in “3- to 7-membered non-aromaticheterocyclyl” mentioned below), respectively. Examples of the bi-cycliccondensed ring include groups of the following formulae.

The “C₆₋₁₀ aryl” means an aromatic hydrocarbon group having 6 to 10carbon atoms, preferably phenyl. The “C₆₋₁₀ aryl” includes, for example,phenyl, 1-naphthyl and 2-naphthyl.

The “C₆₋₁₀ aryl” also includes a condensed ring in which “phenyl” isfused with a 5- or 6-membered ring having one heteroatom selected fromnitrogen, sulfur, or oxygen atom, or the same or different and two ormore (for example, 2 to 4) heteroatoms thereof (for example, “5- or6-membered mono-cyclic heteroaryl” mentioned below, and 5- or 6-memberedring in “3- to 7-membered non-aromatic heterocyclyl” mentioned below),or a 5- to 7-membered cycloalkyl ring (for example, cyclopentane,cyclohexane and cycloheptane). Examples of the condensed ring includegroups of the following formulae.

The “5- to 12-membered heteroaryl” means a 5- to 12-membered mono- ormultiple-cyclic aromatic group having one heteroatom selected fromnitrogen, sulfur, or oxygen atom, or the same or different and two ormore (for example, 2 to 4) heteroatoms thereof, besides carbon atoms asthe ring atoms, preferably, “5- or 6-membered mono-cyclic heteroaryl”The “5- or 6-membered mono-cyclic heteroaryl” means a 5- or 6-memberedmono-cyclic aromatic group within the “5- to 12-membered heteroaryl”.

The multiple-cyclic heteroaryl in the “5- to 12-membered heteroaryl”includes, for example, a condensed ring in which the same or differenttwo mono-cyclic heteroaryls are fused, or a mono-cyclic heteroaryl andan aromatic ring (for example, benzene) or a non-aromatic ring (forexample, cyclohexane) are fused.

The “5- to 12-membered heteroaryl” includes, for example, groups of theformulae shown below. Preferably, the “5- to 12-membered heteroaryl”includes pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, andpyridazinyl. Another embodiment includes, preferably, benzofuranyl inwhich the binding site is on the heteroaryl (furan) ring, pyridyl,pyrimidinyl, pyrazinyl, and pyridazinyl. Examples of the “5- or6-membered mono-cyclic heteroaryl” include mono-cyclic groups out of thegroups of the following formulae.

The “3- to 7-membered non-aromatic heterocyclyl” means 3- to 7-memberedcyclic group having one heteroatom selected from nitrogen, oxygen, orsulfur atom, or the same or different and two or more (for example, 2 to4, preferably 2 to 3) heteroatoms thereof, besides carbon atoms as thering atoms. The heterocyclyl is non-aromatic, which may be a saturatedone or a partially-unsaturated one. Preferred one thereof is a saturatedheterocyclyl, more preferably 5- or 6-membered saturated heterocyclyl.The “3- to 7-membered non-aromatic heterocyclyl” includes, for example,oxetanyl, azetidinyl, pyranyl, tetrahydrofuryl, pyrrolidinyl,pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl,dioxoimidazolidinyl, oxo-oxazolidinyl, dioxo-oxazolidinyl,dioxothiazolidinyl, tetrahydropyranyl, and tetrahydropyridinyl, andpreferably pyranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, andmorpholinyl.

The “3- to 7-membered non-aromatic heterocyclyl” also includes acondensed ring in which the 3- to 7-membered non-aromatic heterocyclylis fused with benzene or a 6-membered heteroaryl (for example, pyridine,pyrimidine or pyridazine) The examples thereof include dihydroindolyl,dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl,dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrolopyridinyl,tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl,decahydroisoquinolinyl, tetrahydronaphthyridinyl, andtetrahydropyrido-azepinyl.

The “C₁₋₂ alkoxy” means oxy group substituted with the above “C₁₋₂alkyl”, and the “C₁₋₄ alkoxy” means oxy group substituted with the above“C₁₋₄ alkyl”. The “C₁₋₂ alkoxy” includes, for example, methoxy andethoxy, and the “C₁₋₄ alkoxy” includes, for example, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy, besides theabove examples. Preferably, the “C₁₋₄ alkoxy” includes methoxy, ethoxy,and isopropoxy.

The “C₃₋₇ cycloalkoxy” means oxy group substituted with the above “C₃₋₇cycloalkyl”. The “C₃₋₇ cycloalkoxy” includes, for example,cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy, andpreferably cyclohexyloxy. The “C₅₋₆ cycloalkoxy” means a cycloalkoxyhaving 5 or 6 carbon atoms within the “C₃₋₇ cycloalkoxy”.

The “C₆₋₁₀ aryloxy” means oxy group substituted with the above “C₆₋₁₀aryl”. The “C₆₋₁₀ aryloxy” includes, for example, phenyloxy andnaphthyloxy, and preferably phenyloxy.

The “5- to 12-membered heteroaryloxy” means oxy group substituted withthe above “5- to 12-membered heteroaryl”. The “5- to 12-memberedheteroaryloxy” includes, for example, pyridyloxy, imidazolyloxy andfuryloxy, and preferably pyridyloxy.

The “C₁₋₄ alkylamino” means amino group substituted with one or two ofthe above “C₁₋₄ alkyl”. The “C₁₋₄ alkylamino” includes, for example,methylamino, ethylamino, propylamino, isopropylamino, butylamino,isobutylamino, dimethylamino, diethylamino, and ethylmethylamino, andpreferably methylamino and dimethylamino.

The “C₃₋₇ cycloalkylamino” means amino group substituted with one or twoof the above “C₃₋₇ cycloalkyl”. The “C₃₋₇ cycloalkylamino” includes, forexample, cyclopropylamino, cyclobutylamino, cyclopentylamino,cyclohexylamino and dicyclopropylamino, and preferably cyclohexylamino.

The “C₁₋₄ alkylsulfonyl” means sulfonyl group substituted with the above“C₁₋₄ alkyl”. The “C₁₋₄ alkylsulfonyl” includes, for example,methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl andbutylsulfonyl, and preferably methylsulfonyl.

The “C₁₋₄ alkylthio” means thio group substituted with the above “C₁₋₄alkyl”. The “C₁₋₄ alkylthio” includes, for example, methylthio,ethylthio, propylthio, isopropylthio and butylthio, and preferablymethylthio.

In order to disclose the present compound of the above formula (I) inmore detail, each symbol used in the present invention is furtherexplained below showing preferred examples.

Preferably, R^(1a), R^(1b), R^(1c), and R^(1d) include independentlyhydrogen, halogen, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino,(wherein each alkyl moiety of the alkyl, the alkoxy and the alkylaminomay be independently substituted with 1 to 3 substituents selectedindependently from the group consisting of halogen, hydroxyl, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₃₋₇ cycloalkoxy optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, and3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B), C₃₋₇cycloalkyl, C₃₋₇ cycloalkoxy, C₃₋₇ cycloalkylamino, (wherein eachcycloalkyl moiety of the cycloalkyl, the cycloalkoxy and thecycloalkylamino may be independently substituted with 1 to 3substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkyl optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB), C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl, and 5- to12-membered heteroaryloxy, (wherein each aryl moiety of the aryl and thearyloxy and each heteroaryl moiety of the heteroaryl and theheteroaryloxy may be independently substituted with 1 to 3 substituentsselected independently from the group consisting of halogen, cyano, C₁₋₄alkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₃₋₇ cycloalkyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, C₃₋₇cycloalkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, 3- to 7-membered non-aromaticheterocyclyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₁₋₄ alkylthiooptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, and C₁₋₄ alkylsulfonyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA), provided that at least one of R^(1a), R^(1b), R^(1c) and R^(1d) isthe above C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl or 5-to 12-membered heteroaryloxy.

More preferably, R^(1a), R^(1b), R^(1c), and R^(1d) includeindependently hydrogen, halogen, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy,(wherein each alkyl moiety of the alkyl and the alkoxy may beindependently substituted with the same or different and 1 to 3halogens), C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl, and5- to 12-membered heteroaryloxy, (wherein each aryl moiety of the aryland the aryloxy and each heteroaryl moiety of the heteroaryl and theheteroaryloxy may be independently substituted with 1 to 3 substituentsselected independently from the group consisting of halogen, cyano, C₁₋₄alkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, and C₁₋₄ alkylsulfonyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA), provided that at least one of R^(1a), R^(1b), R^(1c) and R^(1d) isthe above C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl or 5-to 12-membered heteroaryloxy.

Even more preferably, R^(1a) and R^(1d) include hydrogen, and R^(1b) andR^(1c) are independently hydrogen, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein eacharyl moiety of the aryl and the aryloxy and each heteroaryl moiety ofthe heteroaryl and the heteroaryloxy may be independently substitutedwith 1 to 3 substituents selected independently from the groupconsisting of halogen and optionally-substituted C₁₋₄ alkyl, providedthat both of R^(1b) and R^(1c) are not hydrogen.

In another embodiment of R^(1a), R^(1b), R^(1c), and R^(1d); R^(1a) andR^(1d) are hydrogen, and R^(1b) and R^(1c) are independently hydrogen,C₆₋₁₀ aryloxy, or 5- to 12-membered heteroaryloxy, wherein the arylmoiety of the aryloxy and the heteroaryl moiety of the heteroaryloxy maybe independently substituted with 1 to 3 substituents selectedindependently from the group consisting of halogen andoptionally-substituted C₁₋₄ alkyl, provided that both of R^(1b) andR^(1c) are not hydrogen.

In another embodiment of R^(1a), R^(1b), R^(1c), and R^(1d); R^(1a) andR^(1d) are hydrogen, and R^(1b) and R^(1c) are independently hydrogen,C₆₋₁₀ aryl, or 5- to 12-membered heteroaryl, wherein the aryl and theheteroaryl may be independently substituted with 1 to 3 substituentsselected independently from the group consisting of halogen andoptionally-substituted C₁₋₄ alkyl, provided that both of R^(1b) andR^(1c) are not hydrogen.

In another embodiment of R^(1a), R^(1b), R^(1c), and R^(1d);

R^(1a) and R^(1d) are hydrogen,one of R^(1b) and R^(1c) is C₆₋₁₀ aryloxy or 5- to 12-memberedheteroaryloxy, wherein the aryl moiety of the aryloxy and the heteroarylmoiety of the heteroaryloxy may be independently substituted with 1 to 3substituents selected independently from the group consisting of halogenand optionally-substituted C₁₋₄ alkyl, and the other is hydrogen.

In another embodiment of R^(1a), R^(1b), R^(1c), and R^(1d);

R^(1a) and R^(1d) are hydrogen,one of R^(1b) and R^(1c) is C₆₋₁₀ aryl or 5- to 12-membered heteroaryl,wherein the aryl and the heteroaryl may be independently substitutedwith 1 to 3 substituents selected independently from the groupconsisting of halogen and optionally-substituted C₁₋₄ alkyl, and theother is hydrogen.

Preferred examples of R^(1a), R^(1b), R^(1c), and R^(1d) includehydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl,cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, phenoxy,3-fluorophenoxy, 4-fluorophenoxy, 3,4-difluorophenoxy,3,5-difluorophenoxy, 4-chlorophenoxy, 4-methylphenoxy,4-(trifluoromethyl)phenoxy, 4-methoxyphenoxy,4-(trifluoromethoxy)phenoxy, 4-cyanophenoxy, 4-(methylsulfonyl)phenoxy,(5-methylpyridin-2-yl)oxy, (5-(trifluoromethyl)pyridin-2-yl)oxy, and(5-fluoropyridin-2-yl)oxy.

More preferred examples of R^(1a), R^(1b), R^(1c), and R^(1d) includehydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl,cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl,4-fluorophenyl, 4-(trifluoromethyl)phenyl,5-(trifluoromethyl)pyridin-2-yl, phenoxy, 3-fluorophenoxy,4-fluorophenoxy, 3,4-difluorophenoxy, 3,5-difluorophenoxy,4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl) phenoxy,4-methoxyphenoxy, 4-(trifluoromethoxy) phenoxy, 4-cyanophenoxy,4-(methylsulfonyl)phenoxy, (5-methylpyridin-2-yl)oxy,(5-(trifluoromethyl)pyridin-2-yl)oxy, and (5-fluoropyridin-2-yl)oxy.

Even more preferred examples of R^(1a), R^(1b), R^(1c), and R^(1d)include hydrogen, fluorine, 4-(trifluoromethyl)phenyl,5-(trifluoromethyl)pyridin-2-yl, 3-fluorophenoxy, 4-fluorophenoxy,4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy,4-(trifluoromethoxy)phenoxy, (5-methylpyridin-2-yl)oxy, and(5-(trifluoromethyl)pyridin-2-yl)oxy.

Other embodiments of R^(1a), R^(1b), R^(1c), and R^(1d) includehydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl,cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, phenoxy,3-fluorophenoxy, 4-fluorophenoxy, 3,4-difluorophenoxy,3,5-difluorophenoxy, 4-chlorophenoxy, 4-methylphenoxy,4-(trifluoromethyl)phenoxy, 4-methoxyphenoxy,4-(trifluoromethoxy)phenoxy, 4-cyanophenoxy, 4-(methylsulfonyl)phenoxy,(5-methylpyridin-2-yl)oxy, (5-(trifluoromethyl)pyridin-2-yl)oxy,(5-fluoropyridin-2-yl)oxy, 2-methoxy-4-(trifluoromethyl)phenyl,2-fluoro-4-(trifluoromethyl)phenyl, 2-chloro-4-(trifluoromethyl)phenyl,4-(trifluoromethoxy)phenyl, (5-chloropyridin-2-yl)oxy,2,4-dichlorophenyl, 2-chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy,and 2,4-dichlorophenoxy.

Other embodiments of R^(1a), R^(1b), R^(1c), and R^(1d) includehydrogen, fluorine, 4-(trifluoromethyl)phenyl,5-(trifluoromethyl)pyridin-2-yl, 3-fluorophenoxy, 4-fluorophenoxy,4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy,4-(trifluoromethoxy)phenoxy, (5-methylpyridin-2-yl)oxy,(5-(trifluoromethyl)pyridin-2-yl)oxy,2-methoxy-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, and(5-chloropyridin-2-yl)oxy.

Preferably, R² and R³ include hydrogen and C₁₋₆ alkyl which may besubstituted with 1 to 5 substituents selected independently from thegroup consisting of cyano, halogen, hydroxyl, and C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, and more preferably hydrogen and C₁₋₆ alkyloptionally-substituted with 1 to 5 halogens.

Preferred examples of R² and R³ include hydrogen, methyl, ethyl,isopropyl, isobutyl, trifluoromethyl, cyclopropyl, cyclopentyl, andcyclohexyl, and more preferably hydrogen, methyl, and ethyl.

And, R² and R³ may be combined together with the carbon atom to whichthey are attached to form the following group of formula (II) with —OR⁴.

In the above formula (II), preferably e and f are independently 1 or 2.

Preferably, R^(5a), R^(5b), R^(5c), and R^(5d) are independentlyhydrogen or halogen.

And, R² and R⁷ may be combined together with the carbon atom to whichthey are attached to form the following group of formula (IV) with R³,—OR⁴ and R⁸.

In the above formula (IV), preferably m¹ is 0, and preferably m² is 1 or2.

Preferably, j is 1, 2 or 3.

Preferably, R^(9a), R^(9b), R^(9c), and R^(9d) are independentlyhydrogen or halogen.

Preferably, R⁴ is hydrogen.

Preferably, R⁴ is hydrogen, C₁ 4 alkyl which may be substituted with thesame or different and 1 to 3 halogens, or C₃₋₇ cycloalkyl which may besubstituted with 1 to 3 substituents selected independently from thegroup consisting of halogen, hydroxyl, and C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, and more preferably hydrogen.

Preferred examples of R⁴ include hydrogen, methyl, ethyl, propyl,isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, andmore preferably hydrogen, isopropyl, and cyclopentyl, and even morepreferably hydrogen.

And, R³ and —OR⁴ may be combined together with the carbon atom to whichthey are attached to form the following group of formula (III) with R².

In the above formula (III), preferably h is 1, 2 or 3, and morepreferably 2 or 3.

Preferably, R^(6a), R^(6b) and R^(6c) are independently hydrogen,halogen, or C₁₋₄ alkyl optionally-substituted with the same or differentand 1 to 3 halogens, and more preferably hydrogen.

Preferred examples of R^(6a), R^(6b) and R^(6c) include hydrogen,fluorine, hydroxyl, methyl, trifluoromethyl, methoxy, ethoxy, andtrifluoromethoxy, and more preferably hydrogen, fluorine, and methyl,and even more preferably hydrogen.

Preferably, m is 1 or 2, and more preferably 1.

L is CR⁷R⁸ provided that when m is 2 or 3, each CR⁷R⁸ are independentlythe same or different.

Preferably, R⁷ and R⁸ include hydrogen and C₁₋₄ alkyl which may beindependently substituted with 1 to 3 substituents selectedindependently from the group consisting of halogen, hydroxyl, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₃₋₇ cycloalkoxy optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, and3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, andmore preferably hydrogen.

Preferred examples of R⁷ and R⁸ include hydrogen, methyl, and ethyl, andmore preferably hydrogen.

Preferably, Substituent-group A includes fluorine, chlorine, hydroxyl,C₁₋₂ alkoxy, and C₅₋₆ cycloalkoxy, and more preferably fluorine,hydroxyl, and C₁₋₂ alkoxy.

Preferably, Substituent-group B includes fluorine, chlorine, hydroxyl,C₁₋₂ alkyl, C₁₋₂ alkoxy, and C₅₋₆ cycloalkoxy, and more preferablyfluorine, hydroxyl, C₁₋₂ alkyl, and C₁₋₂ alkoxy.

An embodiment of the compound of formula (I) includes the followingcompound or a pharmaceutically acceptable salt thereof:

R^(1a), R^(1b), R^(1c), and R^(1d) are independently, hydrogen, C₆₋₁₀aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-memberedheteroaryloxy, wherein each aryl moiety of the aryl and the aryloxy andeach heteroaryl moiety of the heteroaryl and the heteroaryloxy may beindependently substituted with 1 to 3 substituents selectedindependently from the group consisting of halogen and C₁₋₄ alkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, provided that at least one of R^(1a), R^(1b),R^(1c) and R^(1d) is the above C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to12-membered heteroaryl or 5- to 12-membered heteroaryloxy,

R² and R³ are independently hydrogen or C₁₋₆ alkyl which may beindependently substituted with 1 to 5 substituents selectedindependently from the group consisting of cyano, halogen, hydroxyl, andC₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, provided that both of R² and R³are not hydrogen, or

R² and R³ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIa) with —OR⁴

in formula (IIa),

e and f are independently 1 or 2,

R⁴ is hydrogen, C₁₋₆ alkyl which may be substituted with 1 to 3substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, or C₃₋₇ cycloalkyl which may be independentlysubstituted with 1 to 3 substituents selected independently from thegroup consisting of halogen, hydroxyl, C₁₋₄ alkyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA, C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB,

V is single bond or oxygen atom,

R^(5a), R^(5b), R^(5c), and R^(5d) are independently hydrogen orhalogen, or

in R², R³, —OR⁴ and CR⁷R⁸ in L,

R² and R⁷ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IVa) with R³, —OR⁴and R⁸

in formula (IVa),

m¹ is 0,

m² is 1 or 2,

j is 1, 2 or 3,

R³ is hydrogen or C₁₋₆ alkyl optionally-substituted with 1 to 3halogens,

R⁴ is hydrogen or C₃₋₇ cycloalkyl optionally-substituted with 1 to 3halogens,

R⁸ is hydrogen, hydroxyl, C₁₋₄ alkyl, C₁₋₄ alkoxy (wherein each alkylmoiety of the alkyl and the alkoxy may be independently substituted with1 to 3 substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B), C₃₋₇ cycloalkyl, or C₃₋₇ cycloalkoxy,(wherein each cycloalkyl moiety of the cycloalkyl and the cycloalkoxymay be independently substituted with 1 to 3 substituents selectedindependently from the group consisting of halogen, hydroxyl, C₁₋₄ alkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, and C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B),

L is CR⁷R⁸, provided that when m is 2, each CR⁷R⁸ are independently thesame or different,

R^(9a), R^(9b), R^(9c), and R^(9d) are independently hydrogen orhalogen,

R⁴ is hydrogen, C₁₋₄ alkyl optionally-substituted with the same ordifferent and 1 to 3 halogens, or C₃₋₇ cycloalkyl which may besubstituted with 1 to 3 substituents selected independently from thegroup consisting of halogen, hydroxyl, and C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, or

R³ and —OR⁴ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIIa) with R²

in formula (IIIa),

h is 1, 2 or 3,

R² is hydrogen, C₁₋₆ alkyl which may be independently substituted with 1to 5 substituents selected independently from the group consisting ofcyano, halogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, and C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, or C₃₋₁₀ cycloalkyl,

R^(6a), R^(6b), and R^(6c) are independently hydrogen, halogen, or C₁₋₄alkyl optionally-substituted with the same or different and 1 to 3halogens,

m is 1 or 2,

L is CR⁷R⁸, provided that when m is 2, each CR⁷R⁸ are independently thesame or different,

R⁷ and R⁸ are independently hydrogen or C₁₋₄ alkyl which may beindependently substituted with 1 to 3 substituents selectedindependently from the group consisting of halogen, hydroxyl, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₃₋₇ cycloalkoxy optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, and3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B.

Another embodiment of the compound of formula (I) includes the followingcompound or a pharmaceutically acceptable salt thereof:

R^(1a) and R^(1d) are hydrogen,

at least one of R^(1b) and R^(1c) is C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein eacharyl moiety of the aryl and the aryloxy and each heteroaryl moiety ofthe heteroaryl and the heteroaryloxy may be independently substitutedwith 1 to 3 substituents selected independently from the groupconsisting of halogen and C₁₋₄ alkyl optionally-substituted with 1 to 3substituents selected independently from Substituent-group A,

R² and R³ are independently C₁₋₆ alkyl optionally-substituted with thesame or different and 1 to 5 halogens, or

R² and R³ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIb) with —OR⁴

in formula (IIb),

e and f are independently 1 or 2,

R⁴ is hydrogen, C₁₋₆ alkyl which may be substituted with 1 to 3substituents selected independently from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, or C₃₋₇ cycloalkyl which may be independentlysubstituted with 1 to 3 substituents selected independently from thegroup consisting of halogen, hydroxyl, C₁₋₄ alkyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA, C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB,

V is single bond or oxygen atom,

R^(5a), R^(5b), R^(5c), and R^(5d) are independently hydrogen orhalogen, or

in R², R³, —OR⁴ and CR⁷R⁸ in L,

R² and R⁷ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IVa) with R³, —OR⁴and R⁸

in formula (IVa),

m¹ is 0,

m² is 1 or 2,

j is 1 or 2,

R³ is hydrogen or C₁₋₄ alkyl,

R⁴ is hydrogen,

R⁸ is hydrogen or C₁₋₄ alkyl,

L is CR⁷R⁸, provided that when m is 2, each CR⁷R⁸ are independently thesame or different,

R^(9a), R^(9b), R^(9c), and R^(9d) are independently hydrogen orhalogen,

R⁴ is hydrogen, C₁₋₄ alkyl optionally-substituted with the same ordifferent and 1 to 3 halogens, or C₃₋₇ cycloalkyl optionally-substitutedwith the same or different and 1 to 3 halogens, or

R³ and —OR⁴ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIIa) with R²

in formula (IIIa),

h is 1, 2 or 3,

R² is hydrogen or C₁₋₄ alkyl optionally-substituted with the same ordifferent and 1 to 3 halogens,

R^(6a), R^(6b), and R^(6c) are independently hydrogen, halogen, or C₁₋₄alkyl optionally-substituted with the same or different and 1 to 3halogens,

m is 1 or 2,

L is CR⁷R⁸, provided that when m is 2, each CR⁷R⁸ are independently thesame or different,

R⁷ and R⁸ are independently hydrogen or C₁₋₄ alkyloptionally-substituted with the same or different and 1 to 3 halogens.

Another embodiment of the compound of formula (I) includes the followingcompound or a pharmaceutically acceptable salt thereof:

R^(1a) and R^(1d) are hydrogen,

one of R^(1b) and R^(1c) is, phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 4-(trifluoromethyl)phenyl,5-(trifluoromethyl)pyridin-2-yl, phenoxy, 3-fluorophenoxy,3,4-difluorophenoxy, 3,5-difluorophenoxy, 4-chlorophenoxy,4-(trifluoromethyl)phenoxy, 4-(trifluoromethoxy)phenoxy, 4-cyanophenoxy,4-(methylsulfonyl)phenoxy, (5-methylpyridin-2-yl)oxy,(5-(trifluoromethyl)pyridin-2-yl)oxy, (5-fluoropyridin-2-yl)oxy,2-methoxy-4-(trifluoromethyl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl,2-chloro-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl,(5-chloropyridin-2-yl)oxy, 2,4-dichlorophenyl, 2-chloro-4-fluorophenoxy,4-chloro-2-fluorophenoxy, or 2,4-dichlorophenoxy, and the other ishydrogen,

both of R² and R³ are methyl, or

R² and R³ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIc) with —OR⁴

in formula (IIc),

e and f are independently 1 or 2,

R⁴ is hydrogen,

V is single bond or oxygen atom, or

R² and R⁷ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IVc) with R³, —OR⁴and R⁸

in formula (IVc),

R³, R⁴, and R⁸ are hydrogen,

m¹ is 0,

m² is 1 or 2,

j is 1 or 2,

L is CR⁷R⁸, and

both of R⁷ and R⁸ are hydrogen,

R⁴ is hydrogen, isopropyl or cyclopentyl, or

R³ and —OR⁴ may be combined together with the carbon atom to which theyare attached to form the following group of formula (IIIb) with R²

in formula (IIIa),

R² is hydrogen, and

h is 2,

m is 1,

L is CR⁷R⁸, and

both of R⁷ and R⁸ are independently hydrogen or methyl.

Processes to prepare the compounds of the present invention arementioned below. The compound (I) of the present invention can beprepared, for example, according to Processes 1 to 5 shown below.

Process 1:

Compound (I) wherein R^(1b) is OR^(a), i.e., Compound (S-5) or apharmaceutically acceptable salt thereof can be prepared, for example,according to the following process.

In the above scheme, R^(1a), R^(1c), R^(1d), R², R³, R⁴, L, and m are asdefined in Term 1; R^(a)O— means R^(1b) which is selected from C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₆₋₁₀ aryloxy optionally-substituted with 1 to3 substituents selected independently from Substituent-group B, or 5- to12-membered heteroaryloxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group B; and X¹ andX² are independently a leaving group such as halogen,trifluoromethanesulfonyloxy, and methanesulfonyloxy.

Step (1-1):

This step is a process to prepare Nitroaniline compound (s-2) byreacting Nitrobenzene compound (s-1) and an amine compound. The baseused herein includes an inorganic base such as sodium hydroxide,potassium hydroxide, potassium carbonate, and cesium carbonate, and anorganic base such as triethylamine, diisopropylethylamine, and DABCO(1,4-diazabicyclo[2,2,2]octane). When the amine compound is used inlarge excess, it is not necessary to use such base. The solvent usedherein includes ethers such as THF, dimethoxyethane, and 1,4-dioxane;DMF; NMP; acetonitrile; and the like. The reaction time is generallyabout 10 minutes to about 10 hours, and the reaction temperature is 0°C. to boiling point of a solvent used herein.

Step (1-2):

This step is a process to prepare Compound (s-3) by reactingNitroaniline compound (s-2) and a compound having hydroxyl. The baseused herein includes sodium hydroxide, potassium hydroxide, potassiumcarbonate, cesium carbonate, sodium hydride, and the like. The solventused herein includes ethers such as THF, 1,2-dimethoxyethane, and1,4-dioxane; DMF; NMP; acetonitrile; and the like. The reaction time isgenerally about 10 minutes to about 10 hours, and the reactiontemperature is 0° C. to boiling point of a solvent used herein.

Step (1-3):

This step is a process to prepare Amino compound (s-4) by reducing Nitrocompound (s-3). The reaction condition of the present step includes ageneral condition to reduce nitro group, for example, catalyticreduction under hydrogenation with palladium-carbon or the like,metallic reduction with zinc, iron or the like, and hydride reductionwith lithium aluminium hydride or the like. The solvent used herein maybe chosen from generally-used solvents depending on each reductioncondition, and includes methanol, ethanol, THF, ethyl acetate, or thelike for catalytic reduction; THF, acetic acid, methanol, ethanol, orthe like for metallic reduction; and diethyl ether, THF, or the like forhydride reduction. The reaction time is generally about 10 minutes toabout 24 hours, and the reaction temperature is 0° C. to boiling pointof a solvent used herein.

Step (1-4):

This step is a process to prepare Compound (S-5) by reactingPhenylenediamine compound (s-4) and formic acid or a formic acidequivalent to be cyclized. The formic acid equivalent includesorthoformates such as methyl orthoformate and ethyl orthoformate. In thepresent step, a catalyst may be used, which includes an organic acidsuch as formic acid and acetic acid, and Lewis acid such as ytterbiumtriflate. The solvent used herein includes alcohols such as methanol andethanol. It is also possible to use formic acid, orthoformate and thelike as a solvent, which are mentioned above as a reactant. The reactiontime is generally about 10 minutes to about 24 hours, and the reactiontemperature is room temperature to boiling point of a solvent usedherein.

Compound (I) wherein any one or more of R^(1a), R^(1b), R^(1c) andR^(1d) is OR^(a) or a pharmaceutically acceptable salt thereof can bealso prepared in a similar manner as the above process.

Process 2:

Compound (I) wherein R⁴ is R^(4a) (alkyl or cycloalkyl), i.e., Compound(S-7) or a pharmaceutically acceptable salt thereof can be prepared, forexample, according to the following process.

In the above scheme, R^(1a), R^(1b), R^(1c), R^(1d), R², R³, L, and mare as defined in Term 1; X³ is the same definition as the above X¹; andR^(4a) is the same as R⁴, provided that hydrogen is excluded.

Step (2-1):

This step is a process to prepare Ether compound (S-7) by reactingAlcohol compound (s-6) which is Compound (s-5) wherein R⁴ is hydrogen,and, for example, a compound of R^(4a)X³ in the presence of a base. Thebase used herein includes sodium hydride, potassium hydride, lithiumhydride, butyllithium, potassium butoxide, and the like. The solventused herein includes ethers such as diethyl ether and THF; DMF; NMP;dimethyl sulfoxide; and the like. The reaction time is generally about10 minutes to about 24 hours, and the reaction temperature is 0° C. toboiling point of a solvent used herein.

Process 3:

Compound (I) wherein R^(1b) is R^(b) (aryl or heteroaryl), i.e.,Compound (S-10) or a pharmaceutically acceptable salt thereof can beprepared, for example, according to the following process.

In the above scheme, R^(1a), R^(1c), R^(1d), R², R³, R⁴, L, and m are asdefined in Term 1; X² is as defined above; and R^(b) is C₆₋₁₀ aryl or 5-to 12-membered heteroaryl, wherein the aryl and the heteroaryl may beindependently substituted with 1 to 5 substituents selectedindependently from the group consisting of halogen, cyano, C₁₋₄ alkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents selected independently from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₁₋₄ alkylthio optionally-substituted with 1to 3 substituents selected independently from Substituent-group A, andC₁₋₄ alkylsulfonyl optionally-substituted with 1 to 3 substituentsselected independently from Substituent-group A.

Step (3-1):

This step is a process to prepare Amino compound (s-8) by selectivelyreducing the nitro group in Nitrobenzene compound (s-2). The reactioncondition of the present step includes catalytic reduction underhydrogenation with sulfur-poisoning platinum-carbon or the like;metallic reduction with zinc, iron, tin or the like; and hydridereduction with lithium aluminium hydride or the like. The solvent usedherein may be chosen from generally-used solvents depending on eachreduction condition, and includes methanol, ethanol, THF, ethyl acetate,or the like for catalytic reduction; THF, acetic acid, methanol,ethanol, or the like for metallic reduction; and diethyl ether, THF, orthe like for hydride reduction. The reaction time is generally about 10minutes to about 24 hours, and the reaction temperature is 0° C. toboiling point of a solvent used herein.

Step (3-2):

This step is a process to prepare Compound (s-9) by treating Aminocompound (s-8) in a similar manner of Step (1-4).

Step (3-3):

This step is a process to prepare Compound (S-10) by reacting Compound(s-9) and a boronic acid compound having R^(b) group or its estercompound in the presence of a base and a catalyst. Specifically, thisstep is a process by means of Suzuki coupling reaction. The base usedherein includes sodium carbonate, potassium carbonate, cesium carbonate,tripotassium phosphate, and the like. The catalyst used herein includespalladium acetate, tetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium, and the like.

The solvent used herein includes 1,4-dioxane, toluene,1,2-dimethoxyethane, and the like. The reaction time is generally about30 minutes to about 24 hours, and the reaction temperature is roomtemperature to boiling point of a solvent used herein.

Compound (I) wherein any one or more of R^(1a), R^(1b), R^(1c) andR^(1d) is R^(b) or a pharmaceutically acceptable salt thereof can bealso prepared in a similar manner as the above process.

Process 4:

Compound (I) wherein R^(1b) is R^(b), i.e., Compound (S-10) or apharmaceutically acceptable salt thereof can be also prepared, forexample, according to the following process.

In the above scheme, R^(1a), R^(1c), R^(1d), R², R³, R⁴, L, and m are asdefined in Term 1; R^(b) and X² are as defined above; and R¹⁰ and R¹¹are independently optionally-substituted C₁₋₄ alkyl,optionally-substituted C₁₋₄ alkoxy, optionally-substituted C₁₋₄dialkylamino, optionally-substituted C₆₋₁₀ aryl, optionally-substitutedC₆₋₁₀ aryloxy, optionally-substituted 5- to 12-membered heteroaryl,optionally-substituted 5- to 12-membered heteroaryloxy, or hydroxyl.Preferably, R¹⁰R¹¹B-includes the following structures, but not limitedthereto.

Step (4-1):

This step is a process to prepare Boronate ester compound (s-11) byreacting Compound (s-9) and a diboron compound such asbis(pinacolato)diboron in the presence of a catalyst and a base. Thecatalyst used herein includesdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium,tetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium, bis(triphenylphosphine)palladiumdichloride, and the like. The base used herein includes potassiumacetate, tripotassium phosphate, potassium carbonate, and the like. Thesolvent used herein includes 1,4-dioxane, toluene, 1,2-dimethoxyethane,and the like. The reaction time is generally about 1 hour to about 48hours, and the reaction temperature is room temperature to boiling pointof a solvent used herein.

Step (4-2):

This step is a process to prepare Compound (S-10) by reacting Boronateester compound (s-11) and a halide compound having R^(b) group or atriflate compound having R^(b) group (such as R^(b)—X (X: halogen atom)or CF₃SO₂O—R^(b)) in the presence of a catalyst and a base.Specifically, this step is a process by means of Suzuki couplingreaction. The base used herein includes sodium carbonate, potassiumcarbonate, cesium carbonate, tripotassium phosphate, and the like. Thecatalyst used herein includes palladium acetate,tetrakis(triphenylphosphine)palladium,tris(dibenzylideneacetone)dipalladium, and the like. The solvent usedherein includes 1,4-dioxane, toluene, 1,2-dimethoxyethane, and the like.The reaction time is generally about 30 minutes to about 48 hours, andthe reaction temperature is room temperature to boiling point of asolvent used herein.

Compound (I) wherein any one or more of R^(1a), R^(1b), R^(1c) andR^(1d) is R^(b) or a pharmaceutically acceptable salt thereof can bealso prepared in a similar manner as the above process.

Process 5:

Compound (I) wherein R^(1b) is OR^(a), i.e., Compound (S-5) or apharmaceutically acceptable salt thereof can be also prepared, forexample, according to the following process.

In the above scheme, R^(1a), R^(1c), R^(1d), R², R³, R⁴, L, and m are asdefined in Term 1; and R^(a), X¹ and X³ are as defined above. Bn meansbenzyl group. Instead of benzyl group, similar protective group tobenzyl group may be also used, for example, substituted benzyl groupwhich is disclosed in Protective Groups in Organic Synthesis.

Step (5-1):

This step is a process to prepare Compound (s-13), for example, byreacting Compound (s-12) with Bn-X³ in the presence of a base. The baseused herein includes sodium carbonate, potassium carbonate, cesiumcarbonate, sodium hydride, and the like. Bn-X³ may include benzylchloride, benzyl bromide and the like. As appropriate, sodium iodide,potassium iodide, tetrabutylammonium iodide, tetrabutylammonium hydrogensulfate, or the like may be added thereto. The solvent used hereinincludes acetone, acetonitrile, THF, diethyl ether, 1,4-dioxane,1,2-dimethoxyethane, DMF, NMP, and the like. The reaction time isgenerally about 30 minutes to about 24 hours, and the reactiontemperature is 0° C. to boiling point of a solvent used herein. Inaddition, Compound (s-13) can be also prepared from Compound (s-12)according to the method (condition) disclosed in Protective Groups inOrganic Synthesis and such.

Step (5-2):

This step is a process to prepare Compound (s-14) from Compound (s-13)in a similar manner of Step (1-1).

Step (5-3):

This step is a process to prepare Compound (s-15) from Compound (s-14)in a similar manner of Step (3-1) (i.e., a manner to selectively reducea nitro group).

Step (5-4):

This step is a process to prepare Compound (s-16) from Compound (s-15)in a similar manner of Step (1-4).

Step (5-5):

This step is a process to prepare Compound (s-17), for example, byhydrogenating Compound (s-16) to deprotect it to the hydroxyl group. Thecatalyst used herein is a heterogenous catalyst such aspalladium-carbon. The condition of hydrogenation means “under hydrogenatmosphere” or “in the presence of formic acid, ammonium formate, or thelike”. The solvent used herein includes methanol, ethanol, THF, ethylacetate, and the like. The reaction time is generally about 30 minutesto about 24 hours, and the reaction temperature is 0° C. to boilingpoint of a solvent used herein. In addition, Compound (s-17) can be alsoprepared from Compound (s-16) according to the method (condition)disclosed in Protective Groups in Organic Synthesis and such.

Step (5-6):

This step is a process to prepare Compound (S-5) from Compound (s-17),which includes the following two reaction conditions, but not limitedthereto.

1) As a reaction condition using a base, it includes a process toprepare Compound (S-5) from Compound (s-17) and R^(a)—X⁴ wherein R^(a)in R^(1b) is C₁₋₄ alkyl optionally-substituted with 1 to 3 substituentsselected independently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, C₆₋₁₀ aryl optionally-substituted with 1 to 3substituents selected independently from Substituent-group B, or 5- to12-membered heteroaryl optionally-substituted with 1 to 3 substituentsselected independently from Substituent-group B, and X⁴ is the same asthe above X¹, according to a similar reaction to Step (1-2).

2) As a reaction condition using a catalyst and a base, it includes aprocess of using a boronic acid compound having R^(a) or a halogencompound having R^(a). The catalyst used herein includes copper (II)acetate, copper (I) iodide, copper (II) oxide, and the like. The baseused herein includes potassium carbonate, cesium carbonate, potassiumhydroxide, triethylamine, and the like. The solvent used herein includeschloroform, 1,4-dioxane, DMF, dimethyl sulfoxide, NMP(N-methyl-2-pyrrolidinone), and the like. The reaction time is generallyabout 30 minutes to about 24 hours, and the reaction temperature is roomtemperature to boiling point of a solvent used herein.

Compound (I) wherein any one or more of R^(1a), R^(1b), R^(1c) andR^(1d) is OR^(a) or a pharmaceutically acceptable salt thereof can bealso prepared in a similar manner as the above process.

The above reduction of nitro group [Step (1-3), Step (3-1), Step (5-3)]and the subsequent cyclization [Step (1-4), Step (3-2), Step (5-4)] canbe sequentially done, for example, by adding formic acid or a formicacid equivalent such as orthoformate in the reduction step (s-3) or(s-14), thus the cyclized compounds (S-5), (s-9), or (s-16) can beprepared in one step. The reaction time is 10 minutes to 12 hours, andthe reaction temperature is room temperature to boiling point of asolvent used herein.

The room temperature in the above processes means specifically 10° C. to30° C.

The starting materials and intermediates in the above processes areknown compounds or can be prepared with known compounds according to aknown method. In case that any functional group other than a targetreaction site can be reacted or can be unsuitable in the aboveprocesses, the functional group other than the target reaction site canbe protected for the reaction, and the protective group can be cleavedto give a desired compound after the reaction is completed. Theprotective group used herein includes, for example, a conventionalprotective group disclosed in the aforementioned Protective Groups inOrganic Synthesis and such. Specifically, the protective group for aminogroup includes, for example, ethoxycarbonyl, tert-butoxycarbonyl,acetyl, benzyl, and the like; and the protective group for hydroxylincludes, for example, tri-lower alkylsilyl, acetyl, benzyl, and thelike.

The introduction and cleavage of protective groups can be done by aconventional method in organic chemistry (for example, see, theaforementioned Protective Groups in Organic Synthesis), or a similarmethod.

By appropriately changing functional group(s) in an intermediate orfinal product in the above processes, it is also possible to prepare adifferent compound defined in the present invention. The conversion offunctional group(s) can be done according to a conventional method (e.g.Comprehensive Organic Transformations, R. C. Larock (1989)).

The intermediates and desired compounds in the above processes can beisolated/purified by a purification generally-used in synthetic organicchemistry, for example, neutralization, filtration, extraction, washing,drying, concentration, recrystallization, various chromatography, etc.Some intermediates can be used in next step without any purification.

The optical isomers of the present invention can be isolated by using aknown division method at an appropriate step, for example, separationwith an optically-active column, and fractionated crystallization. And,it is workable to use an optically-active starting material.

The compounds of the present invention may be sometimes an opticalisomer, a stereoisomer, a tautomer such as a keto-enol compound, and/ora geometric isomer, hence which include all possible isomers includingthe above isomers, and a mixture thereof.

The compounds of the present invention may also include the compound offormula (I), a prodrug thereof, and a pharmaceutically acceptable saltthereof, besides the above isomers. And, the compounds of the presentinvention or a pharmaceutically acceptable salt thereof may be in a formof an adduct with water or each solvent, hence which also include suchadducts. In addition, the compounds of the present invention may alsoinclude various embodiments of the crystals and the compounds in which apart or all of atoms composing the compounds are replaced with anotherisotope (for example, replacing hydrogen with deuterium, and replacing¹²C with ¹⁴C).

The term “prodrug of the compound of formula (I)” used herein means acompound which can be converted to the compound of formula (I) byreacting with an enzyme, gastric acid, etc. under intravitallyphysiological condition, i.e., a compound which can be enzymaticallyoxidized, reduced, hydrolyzed, or taken somehow to be converted to thecompound of formula (I), and a compound which can be hydrolyzed withgastric acid or the like to be converted to the compound of formula (I).

The “pharmaceutically acceptable salt” used herein includes, forexample, a base addition salt or an acid addition salt. The baseaddition salt includes, for example, an alkali metal salt such as sodiumsalt and potassium salt; an alkaline earth metal salt such as calciumsalt and magnesium salt; a water-soluble amine addition salt such asammonium salt and N-methylglucamine (meglumine); and a lower alkanolammonium salt of an organic amine. The acid addition salt includes, forexample, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate,bisulfate, phosphate, acetate, lactate, citrate, tartrate, bitartrate,succinate, maleate, fumarate, gluconate, saccharate, benzoate,methanesulfonate, ethanesulfonate, benzene sulfonate,p-toluenesulfonate, andpamoate[1,1′-methylene-bis-(2-hydroxy-3-naphthoate)].

Salts of the present compound can be prepared, for example, in thefollowing manners. For example, when the present compound is obtained ina salt form, the salt thereof can be prepared by directly purifying it.When the present compound is obtained in a free form, the salt thereofcan be prepared by dissolving or suspending it in an appropriate organicsolvent, adding a possible acid or base thereto, and then treating theobtained mixture in a general manner.

The compound of formula (I) prepared by the above processes may beisolated/purified in a conventional manner such as extraction, columnchromatography, recrystallization, and reprecipitation. The extractionsolvent used herein includes, for example, diethyl ether, ethyl acetate,chloroform, dichloromethane, toluene, and the like. The purification bycolumn chromatography can be done with an acid-, basic-, orvariously-chemical-treating silica gel, alumina, or the like. The elutesolvent used herein includes, for example, hexane/ethyl acetate,hexane/chloroform, ethyl acetate/methanol, chloroform/methanol,acetonitrile/water, methanol/water, and the like.

The novel compounds of the present invention or a pharmaceuticallyacceptable salt thereof having a benzimidazole ring have a propertyinhibiting Nav 1.7 and thereby can be used as a medicament for treatingor preventing a pain involving peripheral nerve such as C-fibres andAδ-fibres, spontaneous pain such as numbness, burning pain, dull pain,pricking pain and shooting pain, neuropathic pain accompanied byhyperalgesia such as mechanical stimulation and cold stimulation orallodynia, nociceptive pain, inflammatory pain, small-fiber neuropathy,erythromelalgia, paroxysmal extreme pain disorder, etc. The neuropathicpain includes, for example, diabetic neuropathy, postherpetic neuralgia,chemotherapy-induced neuropathy, cancer pain, sensory nerve damagecaused by viral infection in human immune deficiency syndrome,trigeminal neuralgia, complex regional pain syndrome, reflex sympatheticdystrophy, neuralgia after low back surgery, phantom limb pain, painafter spinal cord injury, persistent postoperative pain, inflammatorydemyelinating polyradiculopathy, alcoholic neuropathy, entrapmentperipheral neuropathy, iatrogenic neuropathy, sudden sensorineuraldisorder, malnutrition-induced neuropathy, radiation-induced neuropathy,radiculopathy, toxic peripheral neuropathy, traumatic peripheralneuropathy, brachial plexus avulsion injury, glossopharyngeal neuralgia,autoimmune neuropathy, and chronic cauda equina syndrome. Thenociceptive pain or inflammatory pain includes low back pain, abdominalpain, chronic rheumatoid arthritis, a pain caused by osteoarthritis,myalgia, acute postoperative pain, fracture pain, pain after burninjury, and the like. In addition, the present compounds or apharmaceutically acceptable salt thereof can be also used as amedicament for treating or preventing dysuria. The dysuria includesfrequent urination, bladder pain caused by prostatic hyperplasia, andthe like. Furthermore, the present compounds or a pharmaceuticallyacceptable salt thereof can be also used as a medicament for treating orpreventing ataxia developed by suppressing abnormal nervous firing inthe cerebellum in multiple sclerosis. In addition, the present compoundsor a pharmaceutically acceptable salt thereof can be a drug having noside effect in heart or central nerve which is a problem in existingmedication, since they have a selective inhibitory activity to Nav 1.7.

The present compounds may be administered orally, parenterally orrectally, and the daily dose can vary depending on the compound, themode of administration, patient's condition/age, etc. For oraladministration, for example, the present compounds may be administeredgenerally in a dosage of about 0.01 to 1000 mg, preferably about 0.1 to500 mg a day per kilogram of body weight of human or mammal and once toseveral times. For parenteral administration such as intravenousinjection, for example, the present compounds may be administeredgenerally in a dosage of about 0.01 to 300 mg, preferably about 1 to 100mg per kilogram of body weight of human or mammal.

The present compounds can be orally or parenterally administereddirectly or as a suitable formulation comprising it. The formulationthereof may be, for example, tablet, capsule, powder, granule, liquid,suspension, injection, patch, gel patch, and the like, but not limitedthereto. The formulation can be prepared with pharmaceuticallyacceptable additive agents in known means. The additive agents can bechosen for any purpose, including an excipient, a disintegrant, abinder, a fluidizer, a lubricant, a coating agent, a solubilizer, asolubilizing agent, a thickener, dispersant, a stabilizing agent, asweetening agent, a flavor, and the like. Specifically, they include,for example, lactose, mannitol, microcrystalline cellulose,low-substituted hydroxypropylcellulose, cornstarch,partially-pregelatinized starch, carmellose calcium, croscarmellosesodium, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylalcohol, magnesium stearate, sodium stearyl fumarate, polyethyleneglycol, propylene glycol, titanium oxide, talc, and the like.

The present compounds and a pharmaceutically acceptable salt thereof maybe used in combination with, for example, a non-steroidalanti-inflammatory agent such as celecoxib, Voltaren, ibuprofen,loxoprofen, acetaminophen, diclofenac and dexamethasone, and an opioidanalgesic such as tramadol, morphine and oxycodone, in order tostrengthen the action thereof. In addition, the present compounds and apharmaceutically acceptable salt thereof may be also used in combinationwith an antiepileptic agent (such as pregabalin and carbamazepine), analdose reductase inhibitor (such as epalrestat), a prostaglandinderivative drug (such as limaprost alfadex), an antidepressive agent(such as amitriptyline and duloxetine), an anticonvulsant agent, ananxiolytic agent, a dopamine receptor agonist, an antiparkinsonianagent, a hormone preparation, a migraine medication, an adrenergic Rreceptor antagonist, a drug for treating dementia, a drug for treatingmood disorder, or the like. Preferred drugs used in combination with thepresent compound and a pharmaceutically acceptable salt thereof includean antiepileptic agent such as pregabalin and carbamazepine, anantidepressive agent such as amitriptyline and duloxetine, a narcoticanalgesic such as morphine, oxycodone and tramadol, an anti-inflammatoryagent such as acetaminophen, diclofenac and dexamethasone, an aldosereductase inhibitor such as epalrestat, and a prostaglandin derivativesuch as limaprost alfadex. In order to reduce the side effects thereof,the present compounds and a pharmaceutically acceptable salt thereof maybe used in combination with an antiemetic drug and a sleep-inducingdrug. The administration interval of the present compound and itsconcomitant drug is not limited, i.e., the concomitant drug may beadministered at the same time as the present compound or at a suitableinterval. Or, the present compound and its concomitant drug can beformulated into a combination drug. The dose of the combination drug canbe suitably determined based on the standard of the clinically-used dosethereof. The combination ratio of the present compound and itsconcomitant drug can be suitably determined based on its subjectpatient, administration route, disease, pathology, concomitant drug,etc. For example, when the subject patient is a human being, theconcomitant drug may be used in 0.01 to 1000 part by weight per part ofthe present compound.

EXAMPLES

The present invention is explained in more detail in the following byreferring to Examples and Pharmacological tests; however, the technicalscope of the present invention is not limited to such Examples and thelike. The silica gel chromatography or amino silica gel columnchromatography used in the working examples was a product made byYAMAZEN CORPORATION. Each compound was identified with a proton nuclearmagnetic resonance spectrum (¹H-NMR), high-performance liquidchromatograph-mass spectrometer (LCMS), etc. ¹H-NMR was measured withJNM-LA300 (JEOL) or JNM-AL400 (JEOL).

The condition of powder X-ray diffractometry was as follows.

Measuring set: X'pert-MPD (Spectris Co., Ltd.)

X-ray: Cu Kα₁/45 kV/40 mAEntrance slit: 15 mm (Auto)/Divergence-preventing slit: 15 mm (Auto)Sample plate: non-reflecting Si plateStep size: 0.017°Scanning range: 4-40° (2θ)Integration time: 100 seconds/stepHigh-performance liquid chromatography-mass spectrometer: The measuringcondition of LCMS is shown below, and the detected value of massspectrography [MS (m/z)] is shown as M+H.MS detector: ACQITY SQD

HPLC: ACQITY UPLC Column: ACQITY BEH C18 1.7 μm, 2.1×50 mm

Flow rate: 0.75 mL/minWave length: 254 nmMobile phase: A: 0.05% aqueous formic acid

-   -   B: acetonitrile

Time Program:

Step time (min) 1 0.0-1.3 A:B = 90:10 => 1:99 2 1.3-1.5 A:B = 1:99 31.5-2.0 A:B = 90:10

Unless otherwise specified, the starting material compounds, reactionreagents and solvents used herein were commercially available productsor were prepared according to known methods.

In the following Examples and Pharmacological tests, abbreviations shownbelow may be sometimes used to simplify the description of the presentspecification. Me: methyl, Ac: acetyl, Ph: phenyl, THF: tetrahydrofuran,DMF: N,N-dimethylformaldehyde, NMP: N-methyl-2-pyrrolidinone, DMAP:N,N-dimethyl-4-aminopyridine, HEPES:2-[4-(2-hydroxyethyl)-1-piperazinyl]ethanesulfonic acid, EGTA:O,O′-bis(2-aminoethyl)ethylene glycol-N,N,N′,N′-tetraacetate, AD-mix-β:a mixture reagent of hydroquinidine-1,4-phthalazinediyldiether/potassium carbonate/potassium ferricyanide/potassium osmatedihydrate=2/624/624/1 (molar ratio), Pd/C: palladium/carbon, Pt—S/C:sulfur-poisoned platinum/carbon, J: coupling constant, s: singlet, d:doublet, t: triplet, q: quartet, dd: double doublet, td: 3 doublets, tt:3 triplet, m: multiplet, br: broad.

Example 1: Preparation of1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol(Compound 1)

Step (i): Preparation of1-[(5-fluoro-2-nitrophenyl)amino]-2-methylpropan-2-ol (Compound 62)

A mixture of Compound 61 (1.59 g), 1-amino-2-methylpropan-2-ol (0.98 g),diisopropylethylamine (5.22 mL), and DMF (50 mL) was stirred at 60° C.for 2 hours. To the reaction mixture were added water and a mixture ofethyl acetate/hexane (=1/1), and the objective product was extracted inthe organic layer. The organic layer was dried over anhydrous sodiumsulfate and then concentrated under reduced pressure to give Compound 62as a crude product.

Step (ii): Preparation of1-[(5-(4-fluorophenoxy)-2-nitrophenyl]amino)-2-methylpropan-2-ol(Compound 63)

A mixture of the crude product of Compound 62 prepared in Step (i),4-fluorophenol (1.68 g), cesium carbonate (6.52 g), and NMP (25 mL) wasstirred at 100° C. for 2 hours. To the reaction mixture was added waterand a mixture of ethyl acetate/hexane (=1/1), and the objective productwas extracted in the organic layer. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure, andthen the residue was purified by silica gel column chromatography(eluate: hexane/ethyl acetate=3/1) to give Compound 63 (3.10 g).

Step (iii): Preparation of1-{[2-amino-5-(4-fluorophenoxy)phenyl]amino)-2-methylpropan-2-ol(Compound 64)

A mixture of Compound 63 (3.10 g), ammonium formate (2.95 g), 10% Pd/C(0.30 g), and methanol (47 mL) was stirred at 50° C. for 2 hours. Thereaction mixture was filtered through Celite, and the filtrate wasconcentrated under reduced pressure. To the residue were added saturatedaqueous sodium hydrogen carbonate and ethyl acetate, and the objectiveproduct was extracted in the organic layer. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure,and then the residue was purified by silica gel column chromatography(eluate: chloroform/methanol=99/1) to give Compound 64 (2.70 g).

Step (iv): Preparation of1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol(Compound 1)

A mixture of Compound 64 (0.60 g), trimethyl orthoformate (1.73 mL), andp-toluenesulfonic acid monohydrate (0.079 g) was stirred at 60° C. for 1hour. To the reaction mixture were added saturated aqueous sodiumhydrogen carbonate and ethyl acetate, and the objective product wasextracted in the organic layer. The organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure, andthen the residue was purified by silica gel column chromatography(eluate: chloroform/methanol=95/5) to give Compound 1 (0.41 g).

¹H-NMR (DMSO-d6) δ: 1.06 (6H, s), 4.08 (2H, s), 4.72 (1H, s), 6.87 (1H,m), 6.96-6.99 (2H, m), 7.17 (2H, m), 7.39 (1H, m), 7.62 (1H, m), 8.09(1H, s).

XRD; 2θ=12.1, 13.6, 15.0, 15.2, 16.8, 18.5, 19.1, 19.6, 19.9, 20.1,20.7, 21.8, 23.5, 24.0, 24.5, 25.2, 26.0, 26.7, 30.4, 34.8

Example 2: Preparation of6-(4-fluorophenoxy)-1-(tetrahydrofuran-2-ylmethyl)-1H-benzimidazole(Compound 2)

Compound 2 (0.26 g) was prepared according to the process of Example 1by using the starting material, (tetrahydrofuran-2-yl)methanol (0.607 g)instead of 1-amino-2-methylpropan-2-ol.

¹H-NMR (DMSO-d6) δ: 1.49 (1H, m), 1.75 (2H, m), 1.94 (1H, m), 3.63 (2H,m), 4.07-4.34 (3H, m), 6.87-6.90 (1H, m), 6.97-7.02 (2H, m), 7.19 (2H,m), 7.35 (1H, m), 7.62 (1H, m), 8.14 (1H, s).

Example 3: Preparation of6-(4-fluorophenoxy)-1-[2-(propan-2-yloxy)ethyl]-1H-benzimidazole(Compound 3)

A mixture of Compound 65 (0.050 g) prepared according to Example 1 withan appropriate starting material, sodium hydride (0.011 g), and DMF (1.0mL) was stirred at 0° C. for 30 minutes. To the reaction solution wasadded 2-bromopropane (0.045 g), and the mixture was stirred at roomtemperature further for 2 hours. To the reaction mixture were addedsaturated aqueous ammonium chloride, and ethyl acetate, and theobjective product was extracted in the organic layer. The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure, and then the residue was purified by silica gel columnchromatography (eluate: chloroform/methanol=99/1) to give Compound 3 (9mg).

¹H-NMR (DMSO-d6) δ: 0.94 (6H, d, J=6.1 Hz), 3.44 (1H, m), 3.64 (2H, t,J=5.0 Hz), 4.30 (2H, t, J=5.0 Hz), 6.87-7.02 (3H, m), 7.18 (2H, m), 7.32(1H, m), 7.62 (1H, m), 8.13 (1H, s).

Example 4: Preparation of1-[2-(cyclopentyloxy)ethyl]-6-(4-fluorophenoxy)-1H-benzimidazole(Compound 4)

Compound 4 (0.007 g) was prepared according to the process of Example 3by using bromocyclopentane (0.049 g) instead of 2-bromopropane.

LCMS: T=0.828, m/z=341

Example 5: Preparation of1-[6-(4-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol(Compound 5)

Step (i): Preparation of1-[(5-bromo-2-nitrophenyl)amino]-2-methylpropan-2-ol (Compound 67)

Compound 67 (1.20 g) was prepared according to the process of Step (i)in Example 1 by using Compound 66 (1.1 g) instead of Compound 61.

Step (ii): Preparation of1-[(2-amino-5-bromophenyl)amino]-2-methylpropan-2-ol (Compound 68)

Compound 68 (0.811 g) was prepared according to the process of Step(iii) in Example 1 by using Compound 67 (1.20 g) instead of Compound 63,and 3% Pt—S/C (0.24 g) instead of 10% Pd/C as a catalyst.

Step (iii): Preparation of1-(6-bromo-1H-benzimidazol-1-yl)-2-methylpropan-2-ol (Compound 69)

Compound 69 (0.210 g) was prepared according to the process of Step (iv)in Example 1 by using Compound 68 (0.259 g) instead of Compound 64, andacetic acid (0.060 g) instead of p-toluenesulfonic acid monohydrate.

Step (iv): Preparation of1-[6-(4-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol(Compound 5)

A mixture of Compound 69 (0.050 g), 4-fluorophenylboronic acid (0.052g), tetrakis(triphenylphosphine)palladium (0.043 g), and 1,4-dioxane(1.0 mL) was stirred at 80° C. for 1 hour. To the reaction mixture wereadded water and ethyl acetate, and the objective product was extractedin the organic layer. The organic layer was dried over anhydrous sodiumsulfate and concentrated under reduced pressure, and then the residuewas purified by silica gel column chromatography (eluate:chloroform/methanol=99/1) to give Compound 5 (30 mg).

¹H-NMR (DMSO-d6) δ: 1.11 (6H, s), 4.20 (2H, s), 4.79 (1H, s), 7.29 (2H,m), 7.45 (1H, m), 7.66-7.76 (3H, m), 7.94 (1H, s), 8.13 (1H, s).

Examples 6-10

Examples 6 to 10 shown in the following table were prepared according tothe process of Example 5 by using each appropriate starting material.

TABLE 1 Example Chemical Structure Spectrum data 6

LCMS: T = 0.666, m/z = 297 7

LCMS: T = 0.831, m/z = 347 8

¹H-NMR (DMSO-d6) δ: 1.53-1.82 (3H, m), 1.95-2.00 (1H, m), 3.58-3.79 (2H,m), 4.18-4.51 (3H, m), 7.76 (1H, m), 8.06 (1H, m), 8.29 (3H, m), 8.48(1H, s), 9.03 (1H, s). 9

¹H-NMR (DMSO-d6) δ: 1.12 (6H, s), 4.23 (2H, s), 4.81 (1H, s), 7.55 (1H,m), 7.73 (1H, m), 7.82 (2H, m), 7.94 (2H, m), 8.07 (1H, s), 8.18 (1H,s). 10

LCMS: T = 1.055, m/z = 375

Example 11: Preparation of2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol(Compound 11)

Step (i): Preparation of2-methyl-1-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-benzimidazol-1-yl]propan-2-ol(Compound 70)

A mixture of Compound 69 (0.10 g), bis(pinacolato)diboron (0.142 g),dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium (0.054 g),potassium acetate (0.146 g), and 1,4-dioxane (2.0 mL) was stirred at 90°C. for 2 hours. To the reaction mixture were added water and ethylacetate, and the objective product was extracted in the organic layer.The organic layer was dried over anhydrous sodium sulfate andconcentrated under reduced pressure, and then the residue was purifiedby silica gel column chromatography (eluate: hexane/ethyl acetate=8/1)to give Compound 70 (90 mg).

Step (ii): Preparation of2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol(Compound 11)

A mixture of Compound 70 (90 mg), 2-bromo-5-trifluoromethylpyridine(0.126 g), 3 mol/L aqueous sodium carbonate (0.372 mL),tetrakis(triphenylphosphine)palladium (86 mg), and 1,4-dioxane (2 mL)was stirred at 80° C. for 1 hour. To the reaction mixture were addedwater and ethyl acetate, and the objective product was extracted in theorganic layer. The organic layer was dried over anhydrous sodium sulfateand concentrated under reduced pressure, and then the residue waspurified by silica gel column chromatography (eluate: a mixed solvent ofchloroform and methanol) to give Compound 11 (40 mg).

¹H-NMR (DMSO-d6) δ: 1.13 (6H, s), 4.25 (2H, s), 4.83 (1H, s), 7.74 (1H,m), 8.04 (1H, m), 8.24 (3H, m), 8.49 (1H, s), 9.02 (1H, s).

Example 12: Preparation of1-[2-(cyclopentyloxy)ethyl]-6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazole(Compound 12)

Step (i): Preparation of 2-[(5-bromo-2-nitrophenyl)amino]ethan-1-ol(Compound 71)

Compound 71 (0.698 g) was prepared according to the process of Step (i)in Example 5 by using 2-aminoethanol (0.458 g) instead of1-amino-2-methylpropan-2-ol.

Step (ii): Preparation of 2-[(2-amino-5-bromophenyl)amino]ethan-1-ol(Compound 72)

Compound 72 (0.561 g) was prepared according to the process of Step (ii)in Example 5 by using Compound 71 (0.698 g) instead of Compound 67.

Step (iii): Preparation of 2-(6-bromo-1H-benzimidazol-1-yl)ethan-1-ol(Compound 73)

Compound 73 (0.19 g) was prepared according to the process of Step (iii)in Example 5 by using Compound 72 (0.231 g) instead of Compound 68.

Step (iv): Preparation of6-bromo-1-[2-(cyclopentyloxy)ethyl]-1H-benzimidazole (Compound 74)

Compound 74 (0.025 g) was prepared according to the process of Example 3by using Compound 73 (0.19 g) instead of Compound 65.

Step (v): Preparation of1-[2-(cyclopentyloxy)ethyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-benzimidazole(Compound 75)

Compound 75 was prepared according to the process of Step (i) in Example11 by using Compound 74 (0.015 g) instead of Compound 69. The crudeproduct was used in the next step without purification.

Step (vi): Preparation of1-[2-(cyclopentyloxy)ethyl]-6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazole(Compound 12)

Compound 12 (0.018 g) was prepared according to the process of Step (ii)in Example 11 by using Compound 75 instead of Compound 70.

LCMS: T=0.974, m/z=376

Example 13: Preparation of2-methyl-1-(6-phenoxy-1H-benzimidazol-1-yl)propan-2-ol (Compound 13)

Step (i): Preparation of 4-(benzyloxy)-2-fluoro-1-nirobenzene (Compound77)

Under a nitrogen atmosphere, potassium carbonate (27.1 g) was added to asolution of Compound 76 (20.5 g) in DMF (326 mL) at room temperature,and then the mixture was stirred. The reaction mixture was heated to 97°C., and benzyl bromide (27.9 g) was added dropwise thereto over 20minutes. The reaction mixture was stirred further for 1 hour. To thereaction mixture were added ethyl acetate and water, and the objectiveproduct was extracted in the organic layer. The organic layer was washedtwice with water, and then concentrated under reduced pressure. To theobtained residue was added toluene (162 mL), and the mixture wasconcentrated under reduced pressure. (The above extraction procedure wasrepeated twice.) The obtained residue was slurry-washed with a mixtureof ethyl acetate/hexane (=1/4) to give Compound 77 (28.0 g).

Step (ii): Preparation of1-{[5-(benzyloxy)-2-nitrophenyl]amino}-2-methylpropan-2-ol (Compound 78)

Under a nitrogen atmosphere, diisopropylethylamine (32 g) was added to asolution of Compound 77 (24.5 g) in NMP (248 mL) at room temperature.The reaction mixture was heated to 88° C., and1-amino-2-methylpropan-2-ol (11.48 g) was added dropwise thereto over 12minutes. The reaction mixture was stirred further for 1 hour. To thereaction mixture were added ethyl acetate and water, and the objectiveproduct was extracted in the organic layer. The aqueous layer wasextracted with ethyl acetate, and the combined organic layer was washedwith water. The organic layer was concentrated under reduced pressure.To the obtained residue was added toluene (248 mL), and the mixture wasconcentrated under reduced pressure. (The above extraction procedure wasrepeated twice.) To the obtained residue was added water (248 mL)dropwise. The precipitated crystal was collected on a filter, and driedto give Compound 78 (32.8 g).

Step (iii): Preparation of1-[6-(benzyloxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 79)

To a solution of Compound 78 (0.5 g) in methanol (7.9 mL) were addedtrimethyl orthoformate (4.37 mL), formic acid (0.6 mL), and zinc (0.52g), and the mixture was stirred heating at 70° C. for 1 hour. Thereaction mixture was filtered through Celite, and the filtrate wasconcentrated under reduced pressure. To the residue were added a watersolution of Rochelle salt (30 mL) and ethyl acetate (30 mL), and theobjective product was extracted in the organic layer. The organic layerwas washed with brine, dried over anhydrous sodium sulfate, and thenconcentrated under reduced pressure to give Compound 79 (0.45 g).

Step (iv): Preparation of1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-6-ol (Compound 80)

To a solution of Compound 79 (0.5 g) in methanol (5.6 mL) at roomtemperature was added 10% palladium-carbon (50% water-content, 0.1 g),and the mixture was stirred under a hydrogen atmosphere for 4 hours. Thereaction mixture was filtered through Celite, and the filtrate wasconcentrated under reduced pressure. To the obtained residue was addedethyl acetate/hexane, and the mixture was slurry-washed at roomtemperature. The obtained crystal was collected on a filter, and driedto give Compound 80 (0.32 g).

Step (v): Preparation of2-methyl-1-(6-phenoxy-1H-benzimidazol-1-yl)propan-2-ol (Compound 13)

A reaction mixture of Compound 80 (0.10 g), phenylboronic acid (0.118g), copper acetate (0.132 g), triethylamine (0.198 mL), and chloroform(2.5 mL) was stirred at 35° C. for 2 hours. To the reaction mixture wereadded saturated aqueous ammonium chloride, and ethyl acetate, and theobjective product was extracted in the organic layer. The organic layerwas dried over anhydrous sodium sulfate and concentrated under reducedpressure, and then the residue was purified by silica gel columnchromatography (eluate: chloroform/methanol=98/2) to give Compound 13(0.013 g).

¹H-NMR (DMSO-d6) δ: 1.06 (6H, s), 4.08 (2H, s), 4.73 (1H, s), 6.87-6.94(3H, m), 7.05 (1H, m), 7.33 (2H, m), 7.42 (1H, m), 7.62 (1H, m), 8.09(1H, s).

Examples 14-27

Examples 14 to 27 shown in the following table were prepared accordingto the process of Example 13 by using each appropriate startingmaterial.

TABLE 2 Example R^(a)— Spectrum data 14

¹H-NMR (DMSO-d6) δ: 1.06 (6H, s), 2.25 (3H, s), 4.07 (2H, s), 4.72 (1H,s), 6.84 (3H, m), 7.13 (2H, m), 7.36 (1H, m), 7.60 (1H, m), 8.07 (1H,s). 15

¹H-NMR (DMSO-d6) δ: 1.14 (6H, s), 4.11 (2H, s), 4.73 (1H, s), 6.95- 7.08(3H, m), 7.53 (1H, m), 7.68 (3H, m), 8.13 (1H, s). 16

¹H-NMR (CDCl₃) δ: 1.27 (6H, s), 4.12 (2H, s), 6.66 (1H, dt, J = 10.4,2.4 Hz), 6.72-6.79 (2H, m), 7.03 (1H, dd, J = 8.9, 2.1 Hz), 7.13 (1H, d,J = 1.8 Hz), 7.21-7.27 (1H, m), 7.76 (1H, d, J = 8.5 Hz), 8.34 (1H, s).17

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 4.16 (2H, s), 6.42-6.54 (3H, m), 7.06(1H, dd, J = 8.5, 2.4 Hz), 7.17 (1H, d, J = 1.8 Hz), 7.82 (1H, d, J =9.2 Hz), 8.48 (1H, s). 18

¹H-NMR (CDCl₃) δ: 1.27 (6H, s), 4.13 (2H, s), 6.66-6.71 (1H, m),6.77-6.82 (1H, m), 7.00 (1H, dd, J = 8.9, 2.1 Hz), 7.06-7.13 (2H, m),7.77 (1H, d, J = 8.5 Hz), 8.39 (1H, s). 19

¹H-NMR (CDCl₃) δ: 1.27 (6H, s), 3.03 (3H, s), 4.12 (2H, s), 7.01-7.06(3H, m), 7.17-7.26 (1H, m), 7.79 (1H, d, J = 8.5 Hz), 7.85 (2H, d, J =8.5 Hz), 8.28 (1H, s). 20

¹H-NMR (DMSO-d6) δ: 1.07 (6H, s), 4.09 (2H, s), 4.73 (1H, s), 6.89- 6.96(3H, m), 7.37 (2H, m), 7.44 (1H, m), 7.64 (1H, m), 8.11 (1H, s). 21

¹H-NMR (CDCl₃) δ: 1.20 (6H, s), 3.73 (3H, s), 3.96 (2H, s), 6.78-6.82(2H, m), 6.85-6.90 (3H, m), 6.92 (1H, d, J = 1.8 Hz), 7.56 (1H, d, J =9.2 Hz) 7.93 (1H, s). 22

¹H-NMR (CDCl₃) δ: 1.26 (6H, s) 4.08 (2H, s), 6.93-7.00 (3H, m),7.09-7.16 (3H, m), 7.73 (1H, d, J = 8.5 Hz), 8.17 (1H, s). 23

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 4.13 (2H, s), 6.96-6.99 (2H, m), 7.03(1H, dd, J = 8.9, 2.1 Hz), 7.18 (1H, d, J = 1.8 Hz), 7.55-7.59 (2H, m),7.81 (1H, d, J = 8.5 Hz), 8.33 (1H, s). 24

¹H-NMR (DMSO-d6) δ: 1.06 (6H, s), 2.42 (3H, s), 4.08 (2H, s), 4.72 (1H,s), 6.90 (1H, m), 7.23 (2H, m), 7.42 (1H, m), 7.63 (1H, m), 8.09 (1H,s), 8.20 (1H, m). 25

¹H-NMR (DMSO-d6) δ: 1.07 (6H, s), 4.11 (2H, s), 4.73 (1H, s), 7.04 (1H,m), 7.44 (1H, m), 7.60 (1H, m), 7.71 (1H, m), 7.85 (1H, m), 8.15 (1H,s), 8.52 (1H, m). 26

¹H-NMR (DMSO-d6) δ: 1.07 (6H, s), 2.22 (3H, s), 4.09 (2H, s), 4.72 (1H,s), 6.85-6.91 (2H, m), 7.44 (1H, m), 7.59-7.65 (2H, m), 7.94 (1H, m),8.09 (1H, s). 27

¹H-NMR (CDCl₃) δ: 1.25 (6H, s), 1.74 (1H, s), 4.04 (2H, s), 6.96-6.97(1H, m), 7.11-7.12 (1H, m), 7.22- 7.22 (2H, m), 7.73-7.75 (1H, m),7.96-7.97 (1H, m), 8.11-8.11 (1H, m).

Example 28: Preparation of2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol(Compound 28)

A reaction mixture of Compound 80 (1.34 g),2-fluoro-5-(trifluoromethyl)pyridine (1.40 g), cesium carbonate (3.18g), and acetonitrile (22 mL) was stirred at 60° C. for 4 hours. To thereaction mixture were added water and ethyl acetate, and the objectiveproduct was extracted in the organic layer. The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure,and then the residue was purified by silica gel column chromatography(eluate: chloroform/methanol=95/5) to give Compound 28 (1.78 g).

¹H-NMR (DMSO-d6) δ: 1.07 (6H, s), 4.11 (2H, s), 4.73 (1H, s), 7.00 (1H,m), 7.18 (1H, m), 7.56 (1H, m), 7.66 (1H, m), 8.13 (1H, s), 8.20 (1H,m), 8.54 (1H, m).

XRD; 2θ=9.1, 12.9, 13.7, 17.5, 18.0, 18.1, 20.5, 20.8, 21.2, 21.8, 22.3,23.2, 23.8, 24.6, 24.9, 26.9, 27.3, 28.2, 30.2, 32.5.

Examples 29-42

Examples 29 to 42 shown in the following table were prepared accordingto the process of Example 28 by using each appropriate startingmaterial.

TABLE 3 Example R^(a)— Spectrum data 29

¹H-NMR (CDCl₃) δ: 1.22 (6H, s), 4.00 (2H, s), 6.82 (1H, dd, J = 9.2, 3.7Hz), 6.94 (1H, dd, J = 8.9, 2.1 Hz), 7.17 (1H, d, J = 2.4 Hz), 7.33-7.38(1H, m), 7.65 (1H, d, J = 9.2 Hz), 7.89 (1H, s), 7.92 (1H, d, J = 3.1Hz). 30

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 1.65 (1H, s), 4.08 (2H, s), 7.04- 7.08(2H, m), 7.29 (1H, d, J = 1.8 Hz), 7.79 (1H, d, J = 8.5 Hz), 7.97- 7.99(2H, m), 8.24 (1H, dd, J = 4.9, 1.8 Hz). 31

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 1.75 (1H, s), 4.07 (2H, s), 7.04 (1H,dd, J = 8.9, 2.1 Hz), 7.13 (1H, s), 7.17 (1H, d, J = 5.5 Hz), 7.26 (1H,d, J = 2.1 Hz), 7.79 (1H, d, J = 8.9 Hz), 7.97 (1H, s), 8.29 (1H, d, J =5.5 Hz). 32

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 1.69 (1H, s), 4.07 (2H, s), 7.03- 7.05(2H, m), 7.35-7.36 (2H, m), 7.75-7.82 (2H, m), 7.98 (1H, s). 33

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 1.95 (1H, s), 4.07 (2H, s), 6.63 (1H, t,J = 55.8 Hz), 6.97-7.04 (2H, m), 7.26 (1H, d, J = 1.8 Hz), 7.77 (1H, d,J = 8.5 Hz), 7.82 (1H, d, J = 9.2 Hz), 7.95 (1H, s), 8.24 (1H, s). 34

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 1.81 (1H, s), 4.06 (2H, s), 6.86 (1H, d,J = 8.5 Hz), 7.02 (1H, dd, J = 9.2, 1.8 Hz), 7.23 (1H, d, J = 1.8 Hz),7.60-7.63 (1H, m), 7.76 (1H, d, J = 8.5 Hz), 7.95 (1H, s), 8.08 (1H, d,J = 2.4 Hz). 35

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 1.63 (1H, s), 4.08 (2H, s), 7.10 (1H,dd, J = 8.5, 2.1 Hz), 7.30 (1H, d, J = 9.8 Hz), 7.39 (1H, d, J = 2.1Hz), 7.78 (1H, d, J = 9.8 Hz), 7.82 (1H, d, J = 8.5 Hz), 7.98 (1H, s).

TABLE 4 Example R^(a)— Spectrum data 36

¹H-NMR (CDCl₃) δ: 1.29 (6H, s), 1.66 (1H, s), 4.08 (2H, s), 7.06 (1H,dd, J = 8.9, 2.1 Hz), 7.30 (1H, d, J = 2.1 Hz), 7.82 (1H, d, J = 8.9Hz), 7.99 (1H, s), 8.40 (1H, s), 8.49 (1H, s). 37

¹H-NMR (CDCl₃) δ: 1.26 (6H, s), 2.05 (1H, s), 4.03 (2H, s), 7.06 (1H,dd, J = 8.5, 2.4 Hz), 7.15 (1H, d, J = 9.2 Hz), 7.35 (1H, d, J = 2.4Hz), 7.47 (1H, d, J = 9.2 Hz), 7.76 (1H, d, J = 8.5 Hz), 7.93 (1H, s).38

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 1.82 (1H, s), 4.07 (2H, s), 7.03-7.06(1H, m), 7.27-7.27 (1H, m), 7.49-7.51 (1H, m), 7.75-7.77 (1H, m),7.83-7.83 (1H, m), 7.95 (1H, s). 39

¹H-NMR (CDCl₃) δ: 1.29 (6H, s), 1.68 (1H, s), 4.08 (2H, s), 7.07 (1H,dd, J = 8.9, 2.1 Hz), 7.31 (1H, d, J = 2.4 Hz), 7.68 (1H, dd, J = 9.5,2.1 Hz), 7.80 (1H, d, J = 8.9 Hz), 7.98 (1H, s), 8.13 (1H, d, J = 2.4Hz). 40

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 1.81 (1H, s), 4.07 (2H, s), 7.00-7.03(2H, m), 7.26 (1H, d, J = 2.3 Hz), 7.79 (1H, d, J = 8.7 Hz), 7.90 (1H,dd, J = 8.7, 2.3 Hz), 7.97 (1H, s), 8.42-8.43 (1H, m). 41

¹H-NMR (CDCl₃) δ: 1.29 (6H, s), 1.71 (1H, s), 4.08 (2H, s), 7.08 (1H,dd, J = 8.5, 2.4 Hz), 7.31 (1H, d, J = 2.4 Hz), 7.81 (1H, d, J = 8.5Hz), 7.99 (1H, s), 8.77 (2H, s). 42

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 1.70 (1H, s), 4.08 (2H, s), 6.77-6.78(2H, m), 6.98-7.00 (1H, m), 7.19 (1H, d, J = 1.8 Hz), 7.80 (1H, d, J =8.5 Hz), 8.01 (1H, s), 8.19 (1H, d, J = 5.5 Hz).

Example 43: Preparation of2-methyl-1-(5-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol(Compound 43)

Step (i): Preparation of 4-(benzyloxy)-1-chloro-2-nirobenzene (Compound82)

Under a nitrogen atmosphere, potassium carbonate (5.97 g) and benzylbromide (5.91 g) were added to a solution of Compound 81 (5 g) in DMF(56 mL) at room temperature, and then the mixture was stirred for 3hours. To the reaction mixture were added ethyl acetate and water, andthe objective product was extracted in the organic layer. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.After the organic layer was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography (eluate:hexane/ethyl acetate=90/10) to give Compound 82 (7.52 g).

Step (ii): Preparation of1-{[4-(benzyloxy)-2-nitrophenyl]amino}-2-methylpropan-2-ol (Compound 83)

Under a nitrogen atmosphere, diisopropylethylamine (5.53 g) and1-amino-2-methylpropan-2-ol (3.05 g) were added to a solution ofCompound 82 (7.52 g) in NMP (30 mL) at room temperature, and the mixturewas stirred at 100° C. for 1 hour, and then at 150° C. for 1 hour. Thereaction mixture stood to cool at room temperature, anddiisopropylethylamine (5.53 g) and potassium fluoride (1.99 g) wereadded thereto at room temperature. The mixture was stirred at 150° C.for 1 hour, and then at 200° C. for 40 hours. To the reaction mixturewere added ethyl acetate and water, and the objective product wasextracted in the organic layer. The organic layer was washed with brine,and dried over anhydrous sodium sulfate. After the organic layer wasconcentrated under reduced pressure, the residue was purified by silicagel column chromatography (eluate: hexane/ethyl acetate=60/40) to giveCompound 83 (5.3 g).

Step (iii): Preparation of1-[5-(benzyloxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 84)

To a solution of Compound 83 (5.3 g) in methanol (85 mL) were addedtrimethyl orthoformate (44.4 g), formic acid (7.71 g) and zinc (5.48 g),and the mixture was stirred at room temperature for 2 hours. Thereaction mixture was filtered through Celite, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (eluate: chloroform/methanol=95/5) to giveCompound 84 (2.68 g).

Step (iv): Preparation of1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-5-ol (Compound 85)

To a solution of Compound 84 (2.68 g) in methanol (45 mL) was added 10%palladium-carbon (50% water-content, 0.53 g), and the mixture wasstirred under a hydrogen atmosphere for 4 hours. The reaction mixturewas filtered through Celite, and the filtrate was concentrated underreduced pressure. To the obtained residue was added ethyl acetate, andthe mixture was slurry-washed at room temperature. The obtained crystalwas collected on a filter, and dried to give Compound 85 (1.58 g).

Step (v): Preparation of2-methyl-1-(5-{[6-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol(Compound 43)

Under a nitrogen atmosphere, 2-fluoro-6-(trifluoromethyl)pyridine (0.048g) and cesium carbonate (0.118 g) were added to a solution of Compound85 (0.05 g) in NMP (1 mL) at room temperature, and the mixture wasstirred at 100° C. for 3 hours. The reaction mixture was directlypurified by silica gel column chromatography (eluate:chloroform/methanol=95/5) to give Compound 43 (0.064 g).

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.83 (1H, br s), 4.14 (2H, s), 6.98 (1H,d, J=8.7 Hz), 7.13 (1H, dd, J=8.7, 2.3 Hz), 7.35 (1H, d, J=7.3 Hz), 7.45(1H, d, J=8.7 Hz), 7.56 (1H, d, J=1.8 Hz), 7.78 (1H, t, J=8.0 Hz), 8.07(1H, s).

Examples 44-54

Examples 44 to 54 shown in the following table were prepared accordingto the process of Example 43 by using each appropriate startingmaterial.

TABLE 5 Example R³— Spectrum data 44

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.81 (1H, br s), 4.14 (2H, s), 7.00 (1H,d, J = 8.7 Hz), 7.10 (1H, dd, J = 8.9, 2.1 Hz), 7.48 (1H, d, J = 8.7Hz), 7.56 (1H, d, J = 2.3 Hz), 7.87 (1H, dd, J = 8.7, 2.7 Hz), 8.08 (1H,s), 8.40-8.42 (1H, m). 45

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.86 (1H, br s), 4.13 (2H, s), 7.10 (1H,dd, J = 8.7, 2.3 Hz), 7.14 (1H, s), 7.16 (1H, d, J = 5.0 Hz), 7.47 (1H,d, J = 8.7 Hz), 7.55 (1H, d, J = 2.3 Hz), 8.02 (1H, s), 8.29 (1H, d, J =5.0 Hz). 46

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.81 (1H, br s), 4.12 (2H, s), 7.05 (1H,dd, J = 7.3, 5.0 Hz), 7.12 (1H, dd, J = 8.7, 2.3 Hz), 7.46 (1H, d, J =8.7 Hz), 7.57 (1H, d, J = 2.3 Hz), 7.98 (1H, dd, J = 8.0, 1.6 Hz), 8.02(1H, s), 8.25 (1H, dd, J = 5.0, 1.4 Hz). 47

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.86 (1H, br s), 4.11 (2H, s), 6.87-6.90 (1H, m), 6.95 (1H, ddd, J = 7.3, 5.0, 0.9 Hz), 7.10 (1H, dd, J =8.7, 2.3 Hz), 7.44 (1H, d, J = 8.7 Hz), 7.53 (1H, d, J = 2.3 Hz), 7.65(1H, ddd, J = 8.8, 6.7, 1.5 Hz), 8.00 (1H, s), 8.16 (1H, dt, J = 5.0,1.1 Hz). 48

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.80 (1H, br s), 1.80 (0H, s), 4.12 (2H,s), 6.88 (1H, dd, J = 9.1, 3.7 Hz), 7.09 (1H, dd, J = 8.7, 2.3 Hz),7.38-7.46 (2H, m), 7.51 (1H, d, J = 2.3 Hz), 7.99 (1H, d, J = 2.7 Hz),8.03 (1H, s). 49

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.72 (1H, br s), 4.15 (2H, s), 6.87 (1H,d, J = 9.1 Hz), 7.11 (1H, dd, J = 8.7, 2.3 Hz), 7.47 (1H, d, J = 8.7Hz), 7.55 (1H, d, J = 1.8 Hz), 7.62 (1H, dd, J = 8.7, 2.7 Hz), 8.08-8.09 (1H, m), 8.17 (1H, br s). 50

¹H-NMR (CDCl₃) δ: 1.27 (6H, s), 1.88 (1H, br s), 4.12 (2H, s), 7.15 (1H,dd, J = 8.7, 2.3 Hz), 7.32 (1H, d, J = 9.1 Hz), 7.48 (1H, d, J = 8.7Hz), 7.59 (1H, d, J = 2.3 Hz), 7.79 (1H, d, J = 9.1 Hz), 7.96 (1H, s).51

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.76 (1H, br s), 4.15 (2H, s), 7.11 (1H,dd, J = 9.1, 2.3 Hz), 7.51 (1H, d, J = 8.7 Hz), 7.60 (1H, d, J = 2.3Hz), 8.12 (1H, s), 8.40 (1H, d, J = 0.9 Hz), 8.50 (1H, d, J = 0.9 Hz).52

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.77 (1H, br s), 4.15 (2H, s), 7.14 (1H,dd, J = 8.7, 2.3 Hz), 7.51 (1H, d, J = 9.1 Hz), 7.61 (1H, d, J = 1.8Hz), 8.11 (1H, s), 8.77 (2H, d, J = 0.9 Hz). 53

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.70 (1H, br s), 4.16 (2H, s), 7.14 (1H,dd, J = 8.9, 2.1 Hz), 7.50 (1H, d, J = 9.2 Hz), 7.62 (1H, d, J = 2.4Hz), 7.67 (1H, dd, J = 9.5, 2.1 Hz), 8.14 (1H, s), 8.15 (1H, s). 54

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.70 (1H, br s), 4.15 (2H, s), 7.13 (1H,dd, J = 8.7, 2.3 Hz), 7.46- 7.52 (2H, m), 7.58 (1H, d, J = 2.3 Hz), 7.84(1H, d, J = 2.3 Hz), 8.16 (1H, s).

Examples 55-58

Examples 55 to 58 shown in the following table were prepared accordingto the process of Example 59 by using each appropriate startingmaterial.

TABLE 6 Example Chemical Structure Spectrum data 55

¹H-NMR (CDCl₃) δ: 1.48 (2H, d, J = 11.6 Hz), 1.75-1.83 (2H, m), 2.69(1H, br s), 3.72 (2H, td, J = 11.6, 1.8 Hz), 3.80 (2H, td, J = 5.8, 3.7Hz), 4.09 (2H, s), 6.98-7.02 (2H, m), 7.27 (1H, d, J = 1.8 Hz), 7.69(1H, d, J = 8.5 Hz), 7.89 (1H, dd, J = 8.5, 2.4 Hz), 7.89 (1H, s), 8.38(1H, s). 56

¹H-NMR (CDCl₃) δ: 4.39 (1H, br s), 4.51 (2H, s), 4.56 (2H, d, J = 7.9Hz), 4.63 (2H, d, J = 7.9 Hz), 7.00 (2H, td, J = 8.2, 5.9 Hz), 7.36 (1H,d, J = 2.4 Hz), 7.66 (1H, d, J = 8.5 Hz), 7.89 (1H, dd, J = 8.5, 2.4Hz), 7.94 (1H, s), 8.38 (1H, s). 57

¹H-NMR (CDCl₃) δ: 0.83 (2H, dd, J = 6.6, 5.7 Hz), 1.04 (2H, t, J = 6.2Hz), 1.59 (3H, br s), 4.20 (2H, s), 6.87 (1H, dd, J = 8.7, 2.3 Hz), 7.00(1H, d, J = 8.7 Hz), 7.21 (1H, d, J = 1.8 Hz), 7.44 (1H, d, J = 9.1 Hz),7.86-7.89 (2H, m), 8.39 (1H, t, J = 0.9 Hz). 58

¹H-NMR (CDCl₃) δ: 1.63-1.73 (1H, m), 1.84-1.92 (1H, m), 2.06 (2H, q, J =10.6 Hz), 2.17 (2H, q, J = 7.1 Hz), 4.22 (2H, s), 6.99-7.03 (2H, m),7.31 (1H, s), 7.75 (1H, d, J = 8.5 Hz), 7.88 (1H, dd, J = 8.5, 1.8 Hz),8.02 (1H, s), 8.40 (1H, s).

Example 59: Preparation of2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol(Compound 59)

Step (i): Preparation of2-methyl-4-[(2-nitro-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]butan-2-ol(Compound 86)

To a solution of Compound 76 (0.35 g) in NMP (7.5 mL) at roomtemperature was added diisopropylethylamine (1.01 g). To the mixture wasadded 4-amino-2-methylbutan-2-ol hydrochloride (0.37 g), and thereaction solution was heated to 110° C., and stirred for 3.5 hours. Thereaction solution was cooled to room temperature. To reaction solutionwere added cesium carbonate (0.95 g) and2-fluoro-5-(trifluoromethyl)pyridine (0.42 g), and the reaction solutionwas heated to 110° C., and stirred for 4 hours. The reaction solutionwas cooled to room temperature, ethyl acetate and water were addedthereto, and the objective product was extracted in the organic layer.The aqueous layer was extracted with ethyl acetate, and the combinedorganic layer was washed with water. The organic layer was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluate: hexane/ethyl acetate=65/35) to giveCompound 86 (0.6 g).

Step (ii): Preparation of2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol(Compound 59)

To a solution of Compound 86 (0.6 g) in methanol (7.8 mL) were addedtrimethyl orthoformate (4.26 mL), formic acid (0.6 mL) and zinc (0.51g), and the mixture was stirred heating at 70° C. for 2 hours. Thereaction mixture was filtered through Celite, and the filtrate wasconcentrated under reduced pressure. The obtained residue was purifiedby amino silica gel column chromatography (eluate:chloroform/methanol=93/7) to give Compound 59 (0.23 g).

¹H-NMR (CDCl3) δ: 1.31 (6H, s), 2.01-2.05 (2H, m), 4.30-4.34 (2H, m),7.02 (1H, d, J=8.7 Hz), 7.06 (1H, dd, J=8.7, 2.3 Hz), 7.23 (1H, d, J=2.3Hz), 7.82 (1H, d, J=8.7 Hz), 7.89 (1H, dd, J=8.7, 2.7 Hz), 8.04 (1H, s),8.42-8.42 (1H, m).

Example 60: Preparation of2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol(Compound 60)

Step (i): Preparation of1-{6-[(5-formylpyridin-2-yl)oxy]-1H-benzimidazol-1-yl}-2-methylpropan-2-ylAcetate (Compound 87)

To a solution of Compound 80 (0.103 g) in DMF (1 mL) were added6-chloronicotinaldehyde (85 mg) and cesium carbonate (326 mg), and themixture was heated at 110° C. for 1 hour. The reaction mixture wasfiltrated, and DMAP (92 mg) and acetic anhydride (0.142 mL) was added tothe filtrate. The mixture was stirred at room temperature for 3 days. Tothe reaction mixture were added water and ethyl acetate:hexane=2:1(v/v), and the objective product was extracted in the organic layer (theabove extraction procedure was repeated three times). The organic layerwas concentrated under reduced pressure, and then the residue waspurified by silica gel column chromatography (eluate:chloroform/methanol=95/5) to give Compound 87 (130 mg).

Step (ii): Preparation of2-methyl-1-(6-{[5-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ylAcetate (Compound 88)

To a solution of Compound 87 (0.13 g) and trimethyl(trifluoromethyl)silane (0.163 mL) in DMF (3.7 mL) were added potassiumcarbonate (0.025 g) and cesium fluoride (0.056 g), and the mixture wasstirred at room temperature for 2 hours. To the reaction mixture wasadded another trimethyl (trifluoromethyl)silane (0.075 mL), and thereaction mixture was stirred at room temperature further for 1 hour. Tothe reaction mixture were added water and ethyl acetate:hexane=2:1(v/v), and the objective product was extracted in the organic layer (theabove extraction procedure was repeated three times). The organic layerwas concentrated under reduced pressure, and then the residue waspurified by silica gel column chromatography (eluate:chloroform/methanol=95/5) to give Compound 88 (0.106 g).

Step (iii): Preparation of2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ylAcetate (Compound 89)

A solution of Compound 88 (0.1 g) and thiocarbonyldiimidazole (0.051 g)in dry THF (2 mL) was heated under reflux for 2 hours. After allowingthe reaction mixture to stand to cool at room temperature, the reactionmixture was concentrated under reduced pressure. To the residue wereadded ethyl acetate and water, and the objective product was extractedin the organic layer. The organic layer was washed with brine, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure. The obtained residue was dissolved in dry toluene (2 mL) undera nitrogen atmosphere, and then azobisisobutyronitrile (0.008 g) andtri-n-butyltin hydride (0.137 g) were added thereto. The mixture wasstirred at 90° C. for 1 hour. The reaction mixture was concentratedunder reduced pressure, and then the residue was purified by silica gelcolumn chromatography (eluate: chloroform/methanol=95/5) to giveCompound 89 (0.076 mg).

Step (iv): Preparation of2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol(Compound 60)

To a solution of Compound 89 (0.076 mg) in methanol (2 mL) was addedpotassium carbonate (100 mg), and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (eluate:chloroform/methanol=95/5) to give Compound 60 (0.055 g).

¹H-NMR (CDCl₃) 1.22 (6H, s), 3.21-3.29 (2H, m), 4.01 (2H, s), 6.84 (6H,s), 6.94-6.99 (1H, m), 7.21 (2H, s), 7.56 (1H, d, J=8.2 Hz), 7.69 (1H,dd, J=8.7, 2.3 Hz), 7.88 (1H, s), 7.98 (1H, s).

Examples 90-115

Examples 90 to 115 shown in the following table were prepared accordingto the process of Example 1 by using each appropriate starting material.

TABLE 7 Example Chemical Structure Spectrum data 90

¹H-NMR (CDCl₃) δ: 4.54 (2H, s), 4.58 (4H, dd, J = 55.5, 7.9 Hz),6.93-7.05 (5H, m), 7.14 (1H, d, J = 2.4 Hz), 7.64 (1H, d, J = 9.2 Hz),8.27 (1H, d, J = 4.3 Hz). 91

¹H-NMR (CDCl₃) δ: 4.55 (2H, s), 4.58 (4H, dd, J = 53.1, 7.9 Hz),6.89-6.91 (2H, m), 6.99 (1H, dd, J = 9.2, 2.4 Hz), 7.19 (1H, d, J = 1.8Hz), 7.26-7.28 (2H, m), 7.65 (1H, d, J = 8.5 Hz), 8.26 (1H, s). 92

¹H-NMR (CDCl₃) δ: 2.32 (3H, s), 4.52 (2H, s), 4.58 (4H, dd, J = 55.5,7.9 Hz), 6.87- 6.89 (2H, m), 6.98 (1H, dd, J = 8.9, 2.1 Hz), 7.12-7.13(3H, m), 7.60 (1H, d, J = 8.5 Hz), 8.21 (1H, s). 93

¹H-NMR (CDCl₃) δ: 4.50 (2H, s), 4.59 (4H, dd, J = 27.4, 8.2 Hz),6.95-7.00 (3H, m), 7.24-7.25 (1H, m), 7.53 (2H, d, J = 9.1 Hz), 7.64(1H, d, J = 8.7 Hz), 7.96 (1H, s). 94

¹H-NMR (CDCl₃) δ: 4.57 (2H, s), 4.59 (4H, dd, J = 52.5, 7.9 Hz),6.94-7.02 (3H, m), 7.16 (2H, m), 7.23 (1H, d, J = 1.8 Hz), 7.68 (1H, d,J = 8.5 Hz), 8.31 (1H, s). XRD; 20 = 7.7, 11.5, 15.4, 17.4, 17.8, 19.3,21.2, 21.9, 22.5, 23.1, 23.5, 25.6, 26.1, 27.0, 31.0, 32.3, 33.2, 35.0,36.0, 39.0 95

¹H-NMR (CDCl₃) δ: 4.58 (2H, s), 4.59 (4H, dd, J = 54.3, 7.3 Hz), 6.66(1H, dd, J = 10.4, 2.4 Hz), 6.75-6.79 (2H, m), 7.03 (1H, d, J = 9.2 Hz),7.25-7.27 (2H, m), 7.68 (1H, d, J = 8.5 Hz), 8.32 (1H, s). 96

¹H-NMR (CDCl₃) δ: 4.58 (4H, dd, J = 58.0, 7.9 Hz), 4.65 (2H, s), 7.11(1H, dd, J = 8.5, 2.4 Hz), 7.34 (1H, dd, J = 8.9, 2.7 Hz), 7.36 (1H, d,J = 2.4 Hz), 7.63 (1H, d, J = 8.5 Hz), 7.83 (1H, d, J = 9.2 Hz), 8.44(1H, d, J = 3.1 Hz), 8.60 (1H, s). 97

¹H-NMR (CDCl₃) δ: 1.29 (6H, s), 1.99-2.01 (2H, m), 4.28 (2H, t, J = 7.6Hz), 6.94- 6.96 (3H, m), 7.08 (1H, s), 7.15 (2H, m), 7.74 (1H, d, J =8.5 Hz), 7.97 (1H, s). 98

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 2.02 (2H, d, J = 13.4 Hz), 4.27-4.30(2H, br m), 6.66-6.72 (3H, m), 6.99 (1H, d, J = 6.1 Hz), 7.10 (1H, s),7.24 (1H, s), 7.74 (1H, d, J = 7.9 Hz), 7.95 (1H, s). 99

¹H-NMR (CDCl₃) δ: 1.29 (6H, s), 2.00 (2H, t, J = 7.9 Hz), 2.31 (3H, s),4.28 (2H, dd, J = 8.9, 7.0 Hz), 6.89 (2H, m), 6.99 (1H, d, J = 8.5 Hz),7.05 (1H, d, J = 1.8 Hz), 7.11 (2H, m), 7.72 (1H, d, J = 8.5 Hz), 8.12(1H, s). 100

¹H-NMR (CDCl₃) δ: 1.29 (6H, s), 2.00 (2H, t, J = 7.9 Hz), 4.28 (2H, m),6.93-7.03 (6H, m), 7.73 (1H, d, J = 8.5 Hz), 8.07 (1H, s). 101

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.99-2.03 (2H, m), 4.28- 4.32 (2H, m),6.90-6.91 (2H, m), 6.98 (1H, dd, J = 8.5, 2.4 Hz), 7.07 (1H, d, J = 2.4Hz), 7.26-7.27 (2H, m), 7.75 (1H, d, J = 9.2 Hz), 8.12 (1H, br s). XRD;20 = 7.7, 15.3, 16.2, 16.4, 17.0, 18.9, 20.2, 20.3, 20.9, 21.2, 23.7,24.4, 25.4, 27.5, 28.3, 28.6, 29.0, 31.0, 32.0, 34.5 102

¹H-NMR (CDCl₃) δ: 1.26 (6H, s), 1.97-2.01 (2H, m), 4.28- 4.32 (2H, m),6.96-7.01 (3H, m), 7.10 (1H, d, J = 2.4 Hz), 7.51 (2H, m), 7.77 (1H, d,J = 9.2 Hz), 8.27-8.28 (1H, br m). 103

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 2.02-2.08 (2H, m), 4.37 (2H, t, J = 7.9Hz), 7.07 (1H, dd, J = 8.9, 2.1 Hz), 7.19 (1H, d, J = 1.8 Hz), 7.30 (1H,dd, J = 8.9, 2.7 Hz), 7.61 (1H, d, J = 9.2 Hz), 7.86 (1H, d, J = 8.5Hz), 8.40 (1H, s), 8.46 (1H, d, J = 2.4 Hz). 104

¹H-NMR (CDCl₃) δ: 1.27 (6H, s), 3.27-3.35 (2H, m), 4.03 (2H, s),6.90-6.97 (3H, m), 7.09 (1H, d, J = 2.4 Hz), 7.20 (2H, m), 7.67 (1H, d,J = 8.5 Hz), 7.92 (1H, s). 105

¹H-NMR (CDCl₃) δ: 3.31 (2H, q, J = 10.8 Hz), 4.48 (2H, s), 4.59 (4H, dd,J = 27.2, 7.6 Hz), 6.91-6.97 (3H, m), 7.19-7.22 (3H, m), 7.60 (1H, d, J= 8.5 Hz), 7.93 (1H, s). 106

¹H-NMR (DMSO-d6) δ: 4.43 (4H, dd, J = 37.5, 7.0 Hz), 4.51 (2H, s), 6.17(1H, s), 6.91- 6.94 (2H, m), 7.36 (1H, dd, J = 8.5, 2.4 Hz), 7.40 (1H,d, J = 1.8 Hz), 7.64 (1H, d, J = 9.2 Hz), 7.75 (1H, d, J = 2.4 Hz), 8.26(1H, s). 107

¹H-NMR (CDCl₃) δ: 4.08 (1H, s), 4.50 (2H, s), 4.60 (4H, dd, J = 31.0,7.8 Hz), 6.82 (1H, m), 6.93 (1H, m), 7.02 (1H, dd, 2.4, 2.4 Hz), 7.20(1H, dd, J = 2.1, 2.1 Hz), 7.34 (1H, dd, J = 8.9, 2.1 Hz), 7.61 (1H, dd,J = 8.9, 2.1 Hz), 7.94 (1H, d, J = 2.4 Hz). 108

LCMS: T = 0.782, m/z = 399, 401 109

¹H-NMR (CDCl₃) δ: 4.48 (2H, s), 4.58 (4H, dd, J = 23.5, 7.6 Hz),6.89-6.94 (2H, m), 7.03-7.06 (1H, m), 7.12 (1H, d, J = 2.4 Hz), 7.20(1H, dd, J = 10.4, 2.4 Hz), 7.58 (1H, d, J = 9.2 Hz), 7.91 (1H, s). 110

¹H-NMR (CDCl₃) δ: 4.48 (2H, s), 4.57 (4H, dd, J = 11.3, 7.6 Hz), 6.91(3H, m), 7.07 (1H, d, J = 2.4 Hz), 7.20- 7.23 (1H, m), 7.66 (1H, d, J =8.5 Hz), 7.95 (1H, s). 111

¹H-NMR (CDCl₃) δ: 4.19 (1H, br s), 4.51 (2H, s), 4.61 (4H, dd, J = 33.0,7.9 Hz), 6.81 (2H, ,), 6.94 (1H, dd, J = 8.5, 2.4 Hz), 7.03 (1H, dd, J =1.8, 1.8 Hz), 7.22 (1H, d, J = 2.4 Hz), 7.61 (1H, d, J = 8.5 Hz), 7.95(1H, s). 112

¹H-NMR (CDCl₃) δ: 4.51 (2H, s), 4.57-4.59 (4H, m), 6.81 (1H, d, J = 2.4Hz), 6.96- 7.02 (2H, m), 7.20 (1H, d, J = 1.8 Hz), 7.37 (1H, d, J = 8.5Hz), 7.73 (1H, d, J = 8.5 Hz), 8.00 (1H, s). 113

¹H-NMR (DMSO-d6) δ: 1.33 (3H, s), 2.63-2.59 (2H, m), 2.54- 2.50 (2H, m),5.28 (1H, s), 7.00 (1H, dd, J = 8.8, 2.4 Hz), 7.08 (2H, m), 7.54 (1H, d,J = 1.6 Hz), 7.69 (2H, m), 7.71 (1H, d, J = 8.8 Hz), 8.39 (1H, s). 114

¹H-NMR (DMSO-d6) δ: 4.38 (2H, d, J = 6.8 Hz), 4.48 (2H, d, J = 6.8 Hz),4.51 (2H, s), 6.17 (1H, m), 6.97-7.00 (1H, m), 7.23 (1H, d, J = 8.8, 2.4Hz), 7.46 (1H, d, J = 2.4 Hz), 7.54 (1H, d, J = 2.4 Hz), 7.66 (1H, d, J= 8.8 Hz), 8.14 (1H, d, J = 8.8 Hz), 8.26 (1H, s), 9.39 (1H, s). 115

¹H-NMR (DMSO-d6) δ: 4.38 (2H, d, J = 6.8 Hz), 4.48 (2H, d, J = 6.8 Hz),4.52 (2H, s), 6.18 (1H, m), 7.03 (1H, dd, J = 8.4, 2.4 Hz), 7.30 (1H, d,J = 2.4 Hz), 7.46 (1H, dd, J = 8.0, 4.4 Hz), 7.53-7.57 (2H, m),7.68-7.70 (1H, m), 8.01-8.04 (1H, m), 8.20-8.22 (1H, m), 8.28 (1H, s),8.78 (1H, dd, J = 2.0, 4.4 Hz).

Examples 116-121

Examples 116 to 121 shown in the following table were prepared accordingto the process of Example 59 by using each appropriate startingmaterial.

TABLE 8 Example Chemical Structure Spectrum data 116

¹H-NMR (CDCl₃) δ: 1.73 (6H, s), 3.94 (2H, s), 7.00 (2H, m), 7.39 (1H, d,J = 2.4 Hz), 7.70 (1H, d, J = 8.5 Hz), 7.88 (1H, dd, J = 8.9, 2.1 Hz),7.97 (1H, s), 8.40 (1H, s). 117

¹H-NMR (CDCl₃) δ: 1.43-1.54 (2H, m), 1.78-1.92 (2H, m), 2.11-2.22 (4H,m), 3.75 (1H, tt, J = 10.7, 4.4 Hz), 4.11 (1H, tt, J = 12.2, 3.8 Hz),6.97 (1H, d, J = 8.5 Hz), 7.01 (1H, dd, J = 8.5, 2.4 Hz), 7.17 (1H, d, J= 2.4 Hz), 7.77 (1H, d, J = 8.5 Hz), 7.85 (1H, dd, J = 8.9, 2.7 Hz),7.99 (1H, s), 8.37 (1H, d, J = 1.8 Hz). 118

¹H-NMR (CDCl₃) δ: 1.46 (1H, d, J = 2.4 Hz), 1.67-1.76 (2H, m), 1.95-2.03(4H, m), 2.27- 2.36 (2H, m), 4.12-4.19 (2H, m), 7.02 (2H, m), 7.22-7.24(1H, m), 7.82 (1H, d, J = 9.2 Hz), 7.88 (1H, dd, J = 8.5, 2.4 Hz), 8.04(1H, s), 8.42 (1H, s). 119

¹H-NMR (CDCl₃) δ: 1.60-1.87 (8H, m), 4.21 (2H, s), 7.00 (1H, d, J = 8.5Hz), 7.03 (1H, dd, J = 8.5, 2.4 Hz), 7.29 (1H, d, J = 2.4 Hz), 7.78 (1H,d, J = 9.2 Hz), 7.88 (1H, dd, J = 8.5, 2.4 Hz), 8.00 (1H, s), 8.40 (1H,s). 120

¹H-NMR (CDCl₃) δ: 1.28 (6H, s), 1.61 (1H, s), 4.07 (2H, s), 6.94 (1H, d,J = 8.5 Hz), 7.04 (1H, dd, J = 8.5, 2.4 Hz), 7.25 (1H, d, J = 2.4 Hz),7.53-7.57 (1H, m), 7.79 (1H, d, J = 8.5 Hz), 7.96 (1H, s), 8.07 (1H, d,J = 3.1 Hz). 121

¹H-NMR (DMSO-d6) δ: 1.33 (3H, s), 2.59-2.64 (2H, m), 2.51- 2.54 (2H, m),5.28 (1H, s), 7.02-7.04 (1H, m), 7.20 (1H, d, J = 8.8 Hz), 7.56-7.57(1H, m), 7.68 (1H, d, J = 8.8 Hz), 8.21 (1H, dd, J = 2.4, 8.8 Hz), 8.38(1H, s), 8.54-8.55 (1H, m).

Examples 122-174

Examples 122 to 174 shown in the following table were prepared accordingto the process of Example 5 by using each appropriate starting material.

TABLE 9 Example Chemical Structure Spectrum data 122

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 4.27 (2H, s), 7.53 (1H, d, J = 8.5 Hz),7.69 (1H, d, J = 1.2 Hz), 7.76 (1H, d, J = 8.5 Hz), 7.93 (1H, d, J = 8.5Hz), 8.06 (1H, dd, J = 7.9, 1.8 Hz), 8.45 (1H, d, J = 7.9 Hz), 8.96 (1H,d, J = 2.4 Hz). 123

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 4.23 (2H, s), 7.45-7.47 (3H, m), 7.60(1H, dd, J = 7.6, 7.6 Hz), 7.66 (1H, s), 7.88 (1H, d, J = 8.5 Hz), 8.36(1H, s). 124

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 3.84 (3H, s), 4.22 (2H, s), 7.19 (1H,s), 7.30 (1H, d, J = 7.9 Hz), 7.44 (2H, m), 7.62 (1H, s), 7.84 (1H, d, J= 8.5 Hz), 8.38 (1H, s). 125

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 3.97 (3H, s), 4.24 (2H, s), 6.82 (1H, d,J = 8.5 Hz), 7.46 (1H, dd, J = 8.2, 1.5 Hz), 7.57 (1H, s), 7.81 (1H, dd,J = 8.5, 2.4 Hz), 7.85 (1H, d, J = 8.5 Hz), 8.38-8.41 (2H, br m). 126

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 2.62 (3H, s), 4.20 (2H, s), 7.26 (1H, d,J = 9.8 Hz), 7.44 (1H, d, J = 8.5 Hz), 7.65 (1H, s), 7.84-7.86 (2H, m),8.09 (1H, s), 8.74 (1H, s). 127

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 3.57 (4H, t, J = 4.9 Hz), 3.84 (4H, t, J= 4.9 Hz), 4.24 (2H, s), 6.73 (1H, d, J = 8.5 Hz), 7.46 (1H, dd, J =8.2, 1.5 Hz), 7.57 (1H, s), 7.79 (1H, dd, J = 8.5, 2.4 Hz), 7.84 (1H, d,J = 8.5 Hz), 8.39 (1H, s), 8.46 (1H, d, J = 2.4 Hz). 128

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.73 (1H, br s), 3.78 (3H, s), 4.13 (2H,s), 6.69-6.76 (2H, m), 7.28 (1H, dd, J = 7.5, 7.5 Hz), 7.35 (1H, dd, J =8.7, 1.4 Hz), 7.54 (1H, s), 7.78 (1H, d, J = 8.7 Hz), 7.96 (1H, s). 129

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.75 (1H, s), 2.22 (3H, s), 4.11 (2H,s), 7.14-7.20 (3H, m), 7.25 (1H, s), 7.32 (1H, d, J = 1.4 Hz), 7.78 (1H,d, J = 8.2 Hz), 7.99 (1H, s). 130

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.86 (1H, s), 4.14 (2H, s), 7.17-7.23(2H, m), 7.35- 7.43 (2H, m), 7.59-7.59 (1H, br m), 7.81 (1H, d, J = 8.2Hz), 7.99 (1H, s). 131

¹H-NMR (CDCl₃) δ: 1.27 (6H, s), 1.70 (1H, s), 4.10 (2H, s), 7.16 (1H, d,J = 8.2 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.36 (1H, s), 7.51 (1H, d, J =8.2 Hz), 7.72 (1H, s), 7.77 (1H, d, J = 8.2 Hz), 8.01 (1H, s). 133

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.72 (1H, s), 4.13 (2H, s), 7.23-7.33(3H, m), 7.49 (2H, m), 7.81 (1H, d, J = 7.9 Hz), 8.01 (1H, s). 133

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.82 (1H, s), 4.15 (2H, s), 7.14 (1H,m), 7.34-7.40 (3H, m), 7.62 (1H, s), 7.82 (1H, d, J = 8.5 Hz), 8.01 (1H,s). 134

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.82 (1H, s), 4.16 (2H, s), 7.19 (1H,dd, J = 8.9, 8.9 Hz), 7.39 (1H, dd, J = 8.5, 1.8 Hz), 7.42-7.47 (1H, m),7.54 (1H, d, J = 1.8 Hz), 7.62 (1H, dd, J = 6.7, 2.4 Hz), 7.80 (1H, d, J= 8.5 Hz), 7.99 (1H, s). 135

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.79 (1H, br s), 3.10 (3H, s), 4.16 (2H,s), 7.42 (1H, m), 7.66-7.71 (2H, m), 7.77 (2H, m), 7.85 (1H, d, J = 8.5Hz), 8.03 (1H, s). 136

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.80 (1H, s), 4.12 (2H, s), 7.26-7.30(1H, m), 7.47- 7.58 (3H, m), 7.74 (1H, s), 7.79-7.84 (1H, m), 8.00-8.02(1H, m). 137

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.75 (1H, s), 4.18 (2H, s), 7.46-7.63(4H, m), 7.78 (1H, d, J = 7.3 Hz), 7.83-7.85 (2H, m), 8.02 (1H, s). 138

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.58 (1H, s), 4.13 (2H, s), 7.26-7.32(3H, m), 7.36- 7.39 (1H, m), 7.45-7.49 (1H, m), 7.51 (1H, s), 7.79 (1H,d, J = 8.5 Hz), 8.00 (1H, s). 139

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.87 (1H, s), 4.16 (2H, s), 7.28-7.32(1H, m), 7.36 (1H, m), 7.43-7.49 (2H, m), 7.59 (2H, s), 7.80 (1H, d, J =8.2 Hz), 7.99 (1H, s). 140

¹H-NMR (CDCl₃) δ: 1.30 (6H, s), 1.69 (1H, s), 4.13 (2H, s), 7.31-7.37(4H, m), 7.45- 7.49 (1H, m), 7.53 (1H, d, J = 0.9 Hz), 7.81 (1H, d, J =8.2 Hz), 8.01 (1H, s). 141

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.84 (1H, s), 4.17 (2H, s), 7.17-7.20(1H, m), 7.42- 7.47 (3H, m), 7.53 (1H, dd, J = 7.9, 1.2 Hz), 7.59 (1H,d, J = 1.2 Hz), 7.82 (1H, d, J = 8.5 Hz), 8.00 (1H, s). 142

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.76 (1H, s), 3.90 (3H, s), 4.17 (2H,s), 7.09 (1H, s), 7.29 (1H, s), 7.43 (1H, s), 7.46 (1H, dd, J = 8.2, 1.5Hz), 7.59 (1H, s), 7.82 (1H, d, J = 8.5 Hz), 8.01 (1H, s). 143

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.74 (1H, s), 4.17 (2H, s), 7.05 (1H,ddd, J = 8.2, 2.1, 2.1 Hz), 7.21 (1H, ddd, J = 9.8, 1.8, 1.8 Hz), 7.39(1H, dd, J = 1.5, 1.5 Hz), 7.43 (1H, dd, J = 8.5, 1.8 Hz), 7.58 (1H, d,J = 1.8 Hz), 7.82 (1H, d, J = 8.5 Hz), 8.01 (1H, s). 144

¹H-NMR (DMSO-d6) δ: 1.12 (6H, s), 4.16 (2H, s), 4.80 (1H, s), 7.50 (1H,dd, J = 8.4, 2.0 Hz), 7.66 (1H, d, J = 8.4 Hz), 7.99-8.00 (1H, m), 8.13(1H, s), 9.16 (1H, s), 9.40 (1H, s). 145

¹H-NMR (DMSO-d6) δ: 1.14 (6H, s), 4.25 (2H, s), 4.82 (1H, s), 7.54-7.57(1H, m), 7.64-7.67 (1H, m), 7.75 (1H, d, J = 8.0 Hz), 8.10 (1H, d, J =9.2 Hz), 8.15-8.19 (3H, m), 8.29-8.30 (1H, m), 8.43 (1H, dd, J = 8.8,1.2 Hz), 8.88- 8.89 (1H, m). 146

¹H-NMR (DMSO-d6) δ: 1.11 (6H, s), 4.16 (2H, s), 4.77 (1H, s), 6.99-7.00(1H, m), 7.42- 7.44 (1H, m), 7.58-7.61 (1H, m), 7.73-7.74 (1H, m), 7.87(1H, s), 8.08 (1H, s), 8.14- 8.15 (1H, m). 147

¹H-NMR (DMSO-d6) δ: 1.13 (6H, s), 4.23 (2H, s), 4.80 (1H, s), 7.54 (1H,dd, J = 8.4, 2.0 Hz), 7.69 (1H, d, J = 8.4 Hz), 7.77- 7.80 (1H, m), 7.85(1H, d, J = 8.4 H), 8.05 (1H, d, J = 1.2 Hz), 8.12 (1H, d, J = 1.2 Hz),8.14 (1H, s), 8.78 (1H, s). 148

¹H-NMR (DMSO-d6) δ: 3.84 (3H, s), 4.42 (2H, d, J = 6.7 Hz), 4.54 (2H, d,J = 6.7 Hz), 4.59 (2H, s), 6.22 (1H, s), 7.33 (1H, dd, J = 8.2, 1.5 Hz),7.37-7.41 (2H, m), 7.55 (1H, d, J = 7.9 Hz), 7.66 (1H, d, J = 8.5 Hz),7.84 (1H, s), 8.28 (1H, s). XRD; 2θ = 6.6, 13.0, 13.2, 13.6, 15.4, 18.0,18.6, 19.6, 20.0, 21.0, 21.5, 21.8, 23.4, 24.0, 24.9, 25.7, 26.5, 27.5,27.9, 29.3 149

¹H-NMR (CDCl₃) δ: 4.61 (2H, s), 4.65 (4H, dd, J = 20.1, 7.9 Hz), 7.33(1H, m), 7.46 (2H, m), 7.57 (1H, dd, J = 7.9, 7.9 Hz), 7.65 (1H, d, J =8.5 Hz), 7.72 (1H, s), 7.99 (1H, s). 150

¹H-NMR (CDCl₃) δ: 4.59 (2H, s), 4.65 (4H, dd, J = 20.8, 7.9 Hz), 7.23(1H, d, J = 6.7 Hz), 7.48 (1H, d, J = 7.9 Hz), 7.57 (1H, dd, J = 7.9,1.2 Hz), 7.62 (1H, d, J = 1.2 Hz), 7.66 (1H, d, J = 8.5 Hz), 7.75 (1H,d, J = 1.2 Hz), 8.00 (1H, s). 151

¹H-NMR (CDCl₃) δ: 4.56-4.63 (6H, m), 7.14 (1H, dd, J = 8.5, 1.2 Hz),7.30 (1H, d, J = 7.9 Hz), 7.47 (1H, s), 7.52 (1H, dd, J = 8.2, 2.1 Hz),7.68 (1H, d, J = 8.5 Hz), 7.73 (1H, d, J = 2.4 Hz), 8.01 (1H, s). 152

¹H-NMR (CDCl₃) δ: 4.57-4.68 (6H, m), 7.19-7.25 (3H, m), 7.44-7.48 (1H,m), 7.57 (1H, s), 7.62 (1H, d, J = 8.2 Hz), 7.97 (1H, s). 153

¹H-NMR (CDCl₃) δ: 4.57-4.68 (6H, m), 7.18-7.24 (3H, m), 7.45-7.46 (1H,m), 7.57 (1H, s, 7.62 (1H, d, J = 8.2 Hz), 7.97 (1H, s). 154

¹H-NMR (CDCl₃) δ: 4.49-4.58 (6H, m), 7.10 (1H, dd, J = 8.9, 8.9 Hz),7.23 (1H, dd, J = 8.3, 1.5 Hz), 7.31-7.35 (1H, m), 7.48-7.55 (3H, m),7.87 (1H, s). 155

¹H-NMR (CDCl₃) δ: 4.60-4.67 (6H, m), 7.36 (1H, dd, J = 7.9, 1.8 Hz),7.42 (1H, dd, J = 8.6, 2.4 Hz), 7.50 (1H, d, J = 7.9 Hz), 7.65-7.68 (3H,m), 7.99 (1H, s). 156

¹H-NMR (CDCl₃) δ: 4.58 (2H, s), 4.62-4.67 (4H, m), 7.20 (1H, dd, J =8.3, 1.5 Hz), 7.28-7.29 (2H, m), 7.49 (1H, d, J = 1.8 Hz), 7.58 (1H, d,J = 1.2 Hz), 7.62 (1H, d, J = 3.6 Hz), 7.97 (1H, s). 157

¹H-NMR (CDCl₃) δ: 4.59 (2H, s), 4.62-4.66 (4H, m), 7.21- 7.28 (2H, m),7.35 (1H, d, J = 2.4 Hz), 7.40 (1H, d, J = 8.6 Hz), 7.59 (1H, d, J = 1.2Hz), 7.65 (1H, d, J = 8.6 Hz), 7.99 (1H, s). 158

¹H-NMR (CDCl₃) δ: 4.56-4.63 (6H, m), 7.27-7.31 (2H, m), 7.41 (2H, m),7.58-7.61 (2H, m), 7.93 (1H, s). 159

¹H-NMR (CDCl₃) δ: 2.25 (3H, s), 4.01 (1H, br s), 4.57-4.67 (6H, m),7.11-7.18 (3H, m), 7.36 (1H, dd, J = 7.0, 2.7 Hz), 7.43 (1H, d, J = 1.2Hz), 7.65 (1H, d, J = 8.5 Hz), 7.99 (1H, s). 160

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 4.23 (1H, s), 4.58-4.67 (6H, m), 7.13(1H, dd, J = 8.2, 1.5 Hz), 7.17-7.24 (3H, m), 7.44 (1H, d, J = 1.8 Hz),7.64 (1H, d, J = 7.9 Hz), 7.99 (1H, s). 161

¹H-NMR (CDCl₃) δ: 3.80 (1H, s), 4.62-4.67 (6H, m), 7.24- 7.30 (1H, m),7.34 (1H, m), 7.57-7.62 (1H, m), 7.67-7.74 (3H, m), 8.01 (1H, s). 162

¹H-NMR (CDCl₃) δ: 4.30 (1H, s), 4.60-4.69 (6H, m), 7.21- 7.24 (1H, m),7.52-7.66 (5H, m), 8.00 (1H, s). 163

¹H-NMR (CDCl₃) δ: 3.90-3.91 (4H, m), 4.61-4.68 (6H, m), 7.10 (1H, s),7.28 (1H, s), 7.39-7.43 (2H, m), 7.67-7.69 (2H, m), 8.00 (1H, s). 164

¹H-NMR (CDCl₃) δ: 4.19 (1H, s), 4.62-4.69 (6H, m), 7.37- 7.41 (2H, m),7.56-7.68 (4H, m), 7.98 (1H, s). 165

¹H-NMR (CDCl₃) δ: 3.79 (1H, s), 4.60-4.66 (6H, m), 7.06 (1H, m), 7.20(1H, m), 7.36- 7.39 (2H, m), 7.67-7.71 (2H, m), 8.01 (1H, s). 166

¹H-NMR (CDCl₃) δ: 2.30 (3H, d, J = 1.8 Hz), 4.24 (1H, s), 4.57-4.68 (6H,m), 7.11 (1H, dd, J = 8.5, 1.2 Hz), 7.30 (1H, dd, J = 7.9, 7.9 Hz), 7.40(1H, d, J = 7.3 Hz), 7.43 (1H, d, J = 1.2 Hz), 7.63-7.67 (2H, m), 8.00(1H, s). 167

¹H-NMR (CDCl₃) δ: 3.94 (3H, s), 4.51 (1H, s), 4.57 (2H, s), 4.65 (4H,dd, J = 21.7, 7.6 Hz), 6.93-6.97 (2H, m), 7.21-7.28 (2H, m), 7.58-7.60(2H, m), 7.95 (1H, s). 168

¹H-NMR (CDCl₃) δ: 3.91 (1H, s), 4.59-4.66 (6H, m), 7.21 (1H, dd, J =8.2, 1.5 Hz), 7.41 (1H, dd, J = 7.9, 7.9 Hz), 7.53 (1H, dd, J = 7.6, 1.5Hz), 7.58 (1H, d, J = 1.2 Hz), 7.68-7.73 (2H, m), 8.01 (1H, s). 169

¹H-NMR (CDCl₃) δ: 2.40 (3H, s), 4.60-4.72 (6H, m), 4.78 (1H, s), 7.15(1H, s), 7.26 (1H, s), 7.32 (1H, dd, J = 8.5, 1.8 Hz), 7.36 (1H, s),7.53 (1H, d, J = 7.9 Hz), 7.64 (1H, d, J = 1.2 Hz), 7.92 (1H, s). 170

¹H-NMR (CDCl₃) δ: 1.33 (6H, s), 1.41 (1H, s), 2.04-2.06 (2H, m),4.35-4.39 (2H, m), 7.12-7.14 (2H, m), 7.44 (1H, dd, J = 8.5, 1.8 Hz),7.51 (1H, d, J = 1.2 Hz), 7.56-7.59 (2H, m), 7.82 (1H, d, J = 8.5 Hz),7.93 (1H, s). 171

¹H-NMR (CDCl₃) δ: 1.33 (6H, s), 1.41 (1H, s), 2.04-2.06 (2H, m),4.35-4.39 (2H, m), 7.40-7.41 (2H, m), 7.45 (1H, dd, J = 8.2, 1.5 Hz),7.52 (1H, d, J = 1.2 Hz), 7.54-7.56 (2H, m), 7.83 (1H, d, J = 8.5 Hz),7.93 (1H, s). 172

¹H-NMR (CDCl₃) δ: 1.34 (6H, s), 1.36 (1H, s), 2.04-2.06 (2H, m),4.37-4.41 (2H, m), 7.50 (1H, dd, J = 8.5, 1.8 Hz), 7.58 (1H, s), 7.71(4H, m), 7.86 (1H, d, J = 8.5 Hz), 7.96 (1H, s). 173

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.33 (1H, s), 2.02-2.07 (2H, m), 3.86(3H, s), 4.33- 4.37 (2H, m), 7.19 (1H, d, J = 1.2 Hz), 7.30 (1H, dd, J =8.2, 1.5 Hz), 7.40 (1H, dd, J = 8.2, 1.5 Hz), 7.46 (1H, d, J = 7.9 Hz),7.53 (1H, d, J = 1.2 Hz), 7.82 (1H, d, J = 7.9 Hz), 7.94 (1H, s). 174

¹H-NMR (CDCl₃) δ: 1.33 (6H, s), 2.03-2.07 (2H, m), 4.36- 4.40 (2H, m),7.42-7.50 (3H, m), 7.59-7.64 (2H, m), 7.87 (1H, d, J = 8.5 Hz), 7.97(1H, s).

Example 175: Preparation of1-[5-(4-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol(Compound 175)

Step (i): Preparation of1-[(4-bromo-2-nitrophenyl)amino]-2-methylpropan-2-ol (Compound 175b)

Compound 175b (4.81 g) was prepared according to the process of Step (i)in Example 1 by using Compound 175a (5.0 g) instead of Compound 61.

Step (ii): Preparation of1-(5-bromo-1H-benzimidazol-1-yl)-2-methylpropan-2-ol (Compound 175c)

Compound 175c (3.52 g) was prepared according to the process of Step(ii) in Example 59 by using Compound 175b (4.80 g) instead of Compound86.

Step (iii): Preparation of1-[5-(4-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol(Compound 175)

Compound 175 (29 mg) was prepared according to the process of Step (iv)in Example 5 by using Compound 175c (50 mg) instead of Compound 69.

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 4.19 (2H, s), 7.10-7.13 (2H, m), 7.49(2H, m), 7.54-7.57 (2H, m), 7.92 (1H, s), 8.23 (1H, s).

Examples 176-223

Examples 176 to 223 shown in the following table were prepared accordingto the process of Example 175 by using each appropriate startingmaterial.

TABLE 10 Example Chemical Structure Spectrum data 176

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 3.85 (3H, s), 4.20 (2H, s), 7.18 (1H,s), 7.29 (1H, d, J = 7.3 Hz), 7.44 (1H, d, J = 7.9 Hz), 7.46-7.51 (2H,m), 7.95 (1H, s), 8.28 (1H, s). 177

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 3.55-3.57 (4H, m), 3.83- 3.85 (4H, m) ,4.20 (2H, s), 6.73 (1H, d, J = 8.5 Hz), 7.48-7.51 (2H, m), 7.77-7.80(1H, m), 7.91 (1H, s), 8.28 (1H, s), 8.47 (1H, s). 178

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 4.20 (2H, s), 7.38-7.41 (2H, m),7.51-7.55 (4H, m), 7.94 (1H, s), 8.28 (1H, s). 179

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 4.22 (2H, s), 7.28 (2H, m), 7.52 (2H,m), 7.61 (2H, m), 7.96 (1H, d, J = 1.2 Hz), 8.36 (1H, s). 180

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 4.21 (2H, s), 7.55-7.59 (2H, m), 7.74(1H, d, J = 7.9 Hz), 8.01 (1H, d, J = 1.2 Hz), 8.06 (1H, dd, J = 8.2,2.1 Hz), 8.29 (1H, s), 8.96 (1H, d, J = 1.8 Hz). 181

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 4.21 (2H, s), 7.41-7.61 (5H, m), 7.97(1H, s), 8.31 (1H, s). 182

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 3.97 (3H, s), 4.20 (2H, s), 6.82 (1H, d,J = 8.5 Hz), 7.47-7.52 (2H, m), 7.81 (1H, dd, J = 8.5, 1.8 Hz), 7.91(1H, s), 8.28 (1H, s), 8.40 (1H, d, J = 2.4 Hz). 183

¹H-NMR (CDCl₃) δ: 1.27 (6H, s), 2.56 (3H, s), 4.10 (2H, s), 7.17-7.19(1H, m), 7.41- 7.47 (2H, m), 7.76 (1H, dd, J = 8.2, 1.5 Hz), 7.85 (1H,s), 7.98 (1H, s), 8.64 (1H, s). 184

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 4.21 (2H, s), 7.55 (2H, m), 7.68-7.71(4H, m), 8.00 (1H, s), 8.29 (1H, s). 185

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.77 (1H, s), 4.14 (2H, s), 7.29-7.34(3H, m), 7.47- 7.49 (2H, m), 7.80 (1H, d, J = 1.2 Hz), 8.01 (1H, s). 186

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.70 (1H, br s), 3.79 (3H, s), 4.13 (2H,s), 6.69- 6.75 (2H, m), 7.26-7.31 (1H, m), 7.39-7.46 (2H, m), 7.88 (1H,d, J = 1.2 Hz), 7.97 (1H, s). 187

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.73 (1H, s), 2.24 (3H, s), 4.15 (2H,s), 7.16-7.21 (3H, m), 7.25 (1H, s), 7.46 (1H, d, J = 8.5 Hz), 7.67 (1H,d, J = 1.2 Hz), 8.00 (1H, s). 188

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.81 (1H, s), 4.14 (2H, s), 7.17-7.21(2H, m), 7.38- 7.50 (3H, m), 7.89 (1H, s), 8.00 (1H, s). 189

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.77 (1H, s), 4.15 (2H, s), 7.11-7.15(1H, m), 7.33- 7.38 (2H, m), 7.44-7.52 (2H, m), 7.91 (1H, s), 8.00 (1H,s). 190

¹H-NMR (CDCl₃) δ: 1.31 (6H, s), 1.78 (1H, s), 4.14 (2H, s), 7.19 (1H,m), 7.41-7.50 (3H, m), 7.61 (1H, dd, J = 6.7, 2.4 Hz), 7.88 (1H, d, J =1.2 Hz), 8.00 (1H, s). 191

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.64 (1H, s), 4.14 (2H, s), 7.21 (1H, d,J = 8.2 Hz), 7.31 (1H, d, J = 8.2 Hz), 7.44 (1H, d, J = 8.7 Hz), 7.51(1H, d, J = 8.2 Hz), 7.71 (2H, m), 8.02 (1H, br s). 192

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.75 (1H, s), 4.15 (2H, s), 7.34-7.38(1H, m), 7.49- 7.58 (3H, m), 7.74 (1H, s), 7.84 (1H, s), 8.03 (1H, s).193

¹H-NMR (CDCl₃) δ: 1.33 (6H, s), 1.69 (1H, s), 3.14 (3H, s), 4.16 (2H,s), 7.21-7.26 (1H, m), 7.47-7.53 (1H, m), 7.59-7.64 (1H, m), 7.73-7.76(1H, m), 8.04-8.15 (2H, m), 8.33 (1H, br s). 194

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.86 (1H, s), 4.15 (2H, s), 7.51-7.58(4H, m), 7.78 (1H, d, J = 7.3 Hz), 7.84 (1H, s), 7.95 (1H, s), 8.00 (1H,s). 195

¹H-NMR (CDCl₃) δ: 1.33 (6H, s), 1.70 (1H, s), 4.15 (2H, s), 7.25-7.33(2H, m), 7.37 (1H, s), 7.39 (1H, d, J = 1.8 Hz), 7.46-7.49 (2H, m), 7.84(1H, d, J = 1.2 Hz), 8.00 (1H, s). 196

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.78 (1H, s), 4.14 (2H, s), 7.28 (1H,m), 7.35 (1H, dd, J = 7.9, 7.9 Hz), 7.47- 7.51 (3H, m), 7.59 (1H, dd, J= 1.8, 1.8 Hz), 7.93 (1H, s), 7.99 (1H, s). 197

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.73 (1H, s), 4.15 (2H, s), 7.34-7.41(4H, m) , 7.45- 7.49 (2H, m), 7.86 (1H, d, J = 1.2 Hz), 8.00 (1H, s).198

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.80 (1H, s), 4.15 (2H, s), 7.16 (1H, d,J = 8.5 Hz), 7.42-7.55 (5H, m), 7.94 (1H, s), 8.00 (1H, s). 199

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.95 (1H, s), 3.89 (3H, s), 4.15 (2H,s), 7.07 (1H, s), 7.28 (1H, s), 7.42 (1H, s), 7.50 (2H, m), 7.92 (1H,s), 8.00 (1H, s). 200

¹H-NMR (CDCl₃) δ: 1.32 (6H, s), 1.88 (1H, s), 4.14 (2H, s), 7.03 (1H,m), 7.17-7.21 (1H, m), 7.37 (1H, d, J = 1.8 Hz), 7.44-7.52 (2H, m), 7.89(1H, d, J = 1.2 Hz), 8.00 (1H, s). 201

¹H-NMR (DMSO-d6) δ: 1.12 (6H, s), 4.17 (2H, s), 4.80 (1H, s), 7.59 (1H,dd, J = 8.4, 1.6 Hz), 7.73-7.78 (2H, m), 7.83 (1H, d, J = 8.8 Hz), 7.93(1H, d, J = 1.6 Hz), 8.07 (1H, d, J = 1.6 Hz), 8.15 (1H, s), 8.77 (1H,s). 202

¹H-NMR (DMSO-d6) δ: 1.10 (6H, s), 4.15 (2H, s), 4.78 (1H, s), 7.56 (1H,dd, J = 8.4, 1.2 Hz), 7.71 (1H, d, J = 8.4 Hz), 8.01 (1H, d, J = 1.2Hz), 8.13 (1H, s), 9.20 (1H, s), 9.41 (1H, s). 203

¹H-NMR (DMSO-d6) δ: 4.43 (2H, d, J = 6.8 Hz), 4.55 (2H, d, J = 6.8 Hz),4.61 (2H, s), 6.26 (1H, s), 7.46-7.49 (1H, m), 7.65-7.68 (1H, m), 7.77-7.86 (4H, m), 8.35 (1H, s). 204

¹H-NMR (DMSO-d6) δ: 4.43 (2H, d, J = 7.2 Hz), 4.54 (2H, d, J = 7.2 Hz),4.59 (2H, s), 6.25 (1H, s), 7.43 (2H, m), 7.57 (1H, dd, J = 8.4, 2.0Hz), 7.78 (1H, d, J = 8.4 Hz), 7.81-7.84 (2H, m), 7.92- 7.91 (1H, m),8.30 (1H, s). 205

¹H-NMR (CDCl₃) δ: 3.84 (3H, s), 4.58-4.65 (6H, m), 7.17 (1H, s), 7.27(1H, d, J = 7.9 Hz), 7.39 (1H, d, J = 7.3 Hz), 7.45 (1H, dd, J = 8.5,1.2 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.85 (1H, d, J = 1.8 Hz), 8.00 (1H,s). 206

¹H-NMR (CDCl₃) δ: 4.60-4.66 (6H, m), 7.38 (1H, dd, J = 8.2, 1.5 Hz),7.46 (1H, d, J = 7.9 Hz), 7.56 (1H, dd, J = 7.9, 1.2 Hz), 7.61 (1H, d, J= 7.9 Hz), 7.74 (1H, d, J = 1.2 Hz), 7.78 (1H, d, J = 1.2 Hz), 8.05 (1H,s). 207

¹H-NMR (CDCl₃) δ: 4.59-4.65 (6H, m), 7.22-7.27 (2H, m), 7.51 (1H, dd, J= 8.2, 2.1 Hz), 7.55 (1H, d, J = 8.5 Hz), 7.65 (1H, s), 7.72 (1H, d, J =1.8 Hz), 8.02 (1H, s). 208

¹H-NMR (CDCl₃) δ: 2.25 (3H, s), 3.65 (1H, br s), 4.60- 4.66 (6H, m),7.09-7.16 (2H, m), 7.21 (1H, dd, J = 8.5, 1.6 Hz), 7.35 (1H, dd, J =7.8, 1.8 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 0.9 Hz), 8.03(1H, s). 209

¹H-NMR (CDCl₃) δ: 2.19 (3H, s), 3.59 (1H, s), 4.59-4.67 (6H, m),7.16-7.24 (4H, m), 7.56 (1H, d, J = 8.7 Hz), 7.60 (1H, d, J = 0.9 Hz),8.01 (1H, s). 210

¹H-NMR (CDCl₃) δ: 3.37 (1H, d, J = 7.3 Hz), 4.61-4.66 (6H, m), 7.22-7.27(1H, m), 7.47 (1H, m), 7.54-7.59 (1H, m), 7.62 (1H, d, J = 8.5 Hz), 7.68(1H, dd, J = 7.3, 1.8 Hz), 7.84 (1H, s), 8.02 (1H, s). 211

¹H-NMR (CDCl₃) δ: 3.83 (1H, s), 4.61-4.68 (6H, m), 7.37 (1H, dd, J =8.5, 1.2 Hz), 7.50-7.62 (4H, m), 7.71 (1H, d, J = 1.8 Hz), 8.02 (1H, s).212

¹H-NMR (CDCl₃) δ: 3.87 (3H, s), 4.27 (1H, s), 4.60 (2H, s), 4.68 (4H,dd, J = 21.1, 7.6 Hz), 7.05 (1H, s), 7.17 (1H, s), 7.30 (1H, s), 7.46(1H, dd, J = 8.5, 1.8 Hz), 7.59 (1H, d, J = 8.5 Hz), 7.68 (1H, d, J =1.2 Hz), 7.94 (1H, s). 213

¹H-NMR (CDCl₃) δ: 4.46 (1H, s), 4.60 (2H, s), 4.69 (4H, dd, J = 23.5,7.5 Hz), 7.35 (1H, s), 7.43-7.49 (3H, m), 7.58 (1H, d, J = 8.7 Hz), 7.64(1H, s), 7.92 (1H, s). 214

¹H-NMR (CDCl₃) δ: 3.45 (1H, s), 4.59-4.67 (6H, m), 7.03 (1H, m), 7.14(1H, m), 7.32 (1H, s), 7.45 (1H, dd, J = 8.5, 1.6 Hz), 7.59 (1H, d, J =8.7 Hz), 7.78 (1H, s), 7.99 (1H, s). 215

¹H-NMR (CDCl₃) δ: 2.30 (3H, d, J = 1.2 Hz), 3.80 (1H, s), 4.61-4.67 (6H,m), 7.20 (1H, dd, J = 8.2, 1.5 Hz), 7.29 (1H, dd, J = 7.6, 7.6 Hz), 7.36(1H, d, J = 6.7 Hz), 7.56-7.64 (3H, m), 8.03 (1H, s). 216

¹H-NMR (CDCl₃) δ: 3.27 (1H, s), 3.94 (3H, s), 4.60-4.65 (6H, m), 6.95(2H, m), 7.24- 7.28 (1H, m), 7.39 (1H, dd, J = 8.2, 1.5 Hz), 7.57 (1H,d, J = 8.5 Hz), 7.78 (1H, d, J = 1.8 Hz), 8.01 (1H, s). 217

¹H-NMR (CDCl₃) δ: 3.23 (1H, br s), 4.61-4.64 (7H, m), 7.35 (1H, dd, J =8.2, 1.5 Hz), 7.40 (1H, m), 7.52 (1H, dd, J = 7.9, 1.2 Hz), 7.60 (1H, d,J = 8.5 Hz), 7.70 (1H, dd, J = 7.9, 1.8 Hz), 7.75 (1H, d, J = 1.2 Hz),8.05 (1H, s). 218

¹H-NMR (CDCl₃) δ: 2.36 (3H, s), 4.56-4.73 (6H, m), 7.13 (2H, m),7.23-7.25 (1H, m), 7.41 (1H, dd, J = 8.2, 1.5 Hz), 7.55 (1H, d, J = 8.5Hz), 7.61 (1H, d, J = 1.8 Hz), 7.89 (1H, s). 219

¹H-NMR (CDCl₃) δ: 1.34 (6H, s), 1.37 (1H, s), 2.03-2.08 (2H, m),4.34-4.38 (2H, m), 7.11-7.13 (2H, m), 7.44-7.50 (2H, m), 7.56-7.58 (2H,m), 7.93 (2H, s). 220

¹H-NMR (CDCl₃) δ: 1.33 (6H, s), 1.35 (1H, s), 2.04-2.06 (2H, m),4.34-4.38 (2H, m), 7.39-7.41 (2H, m), 7.44-7.50 (2H, m), 7.53-7.57 (2H,m), 7.94 (1H, s), 7.95 (1H, s). 221

¹H-NMR (CDCl₃) δ: 1.34 (6H, s), 1.38 (1H, s), 2.04-2.08 (2H, m),4.35-4.39 (2H, m), 7.48-7.55 (2H, m), 7.67-7.74 (4H, m), 7.96 (1H, s),8.01 (1H, d, J = 1.2 Hz). 222

¹H-NMR (CDCl₃) δ: 1.34 (6H, s), 2.04-2.08 (2H, m), 3.85 (3H, s),4.34-4.38 (2H, m), 7.18 (1H, s), 7.29 (1H, d, J = 7.9 Hz), 7.45-7.46(3H, m), 7.94 (2H, s). 223

¹H-NMR (CDCl₃) δ: 1.34 (6H, s), 2.04-2.08 (2H, m), 4.36- 4.40 (2H, m),7.42-7.48 (4H, m), 7.59-7.61 (1H, m), 7.96- 7.97 (2H, m).

Example 224: Preparation of1-{5-[2-fluoro-4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol

Compound 224 (13 mg) was prepared according to the process of Step (v)in Example 13 by using Compound 85 (50 mg).

LCMS: T=0.743, m/z=369

Examples 225 and 226

Examples 225 and 226 shown in the following table were preparedaccording to the process of Example 224 by using each appropriatestarting material.

TABLE 11 Example Chemical Structure Spectrum data 225

¹H-NMR (DMSO-d6) δ: 1.11 (6H, s), 4.16 (2H, s), 4.79 (1H, s), 7.03-7.07(3H, m), 7.39 (1H, d, J = 2.4 Hz), 7.68 (2H, m), 7.73 (1H, d, J = 8.4Hz), 8.17 (1H, s). 226

¹H-NMR (DMSO-d6) δ: 4.43 (2H, d, J = 7.2 Hz), 4.54 (2H, d, J = 7.2 Hz),4.58 (2H, s), 6.25 (1H, s), 7.05-7.07 (3H, m), 7.40 (1H, d, J = 2.8 Hz),7.68 (1H, d, J = 9.2 Hz), 7.76 (1H, d, J = 9.2 Hz), 8.32 (1H, s).

Example 227: Preparation of(2R)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propane-1,2-diol

Step (i): Preparation ofN-(2-methylprop-2-en-1-yl)-2-nitro-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}aniline(Compound 227a)

Compound 227a (1.64 g) was prepared according to the process of Step (i)in Example 59 by using the appropriate starting material.

Step (ii): Preparation of1-(2-methylprop-2-en-1-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazole(Compound 227b)

Compound 227b (1.25 g) was prepared according to the process of Step(ii) in Example 59 by using Compound 227a.

Step (iii): Preparation of(2R)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propane-1,2-diol(Compound 198)

Under a nitrogen atmosphere, water (1 mL), AD-mix-β (200 mg) andmethanesulfonamide (14 mg) were added to a solution of Compound 227b (50mg) in tert-butanol (1 mL), and the reaction mixture was stirred at roomtemperature for 5 hours. The reaction mixture was directly purified byamino silica gel column chromatography (eluate:chloroform/methanol=95/5) to give Compound 227 (26 mg).

LCMS: T=0.537, m/z=368

Example 228: Preparation of(3R)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol

Step (i): Preparation of tert-butyl[(2R)-3-hydroxy-3-methylbutan-2-yl]carbamate (Compound 228b)

Under a nitrogen atmosphere, 3 mol/L methylmagnesium bromide/diethylether (5.90 mL) was added to a solution of Boc-D-alanine methyl ester(1.0 g) in diethyl ether (25 mL) at 0° C., and the mixture was stirredat room temperature for 3 hours. The reaction mixture was quenched withaqueous ammonium chloride and then extracted with ethyl acetate, and theorganic layer was dried over anhydrous sodium sulfate. The concentratedresidue was purified by silica gel column chromatography (eluate:hexane/ethyl acetate=70/30) to give Compound 228b (0.86 g).

Step (ii): Preparation of (3R)-3-amino-2-methylbutan-2-olMonohydrochloride (Compound 228c)

Under a nitrogen atmosphere, 4 mol/L hydrocholic acid/ethyl acetate wasadded to a solution of Compound 228b (0.86 g) in ethyl acetate (5 mL),and the mixture was stirred at room temperature for 2 hours. The solventin reaction mixture was removed by azeotropy with toluene, and theobtained residue was slurry-washed with ethyl acetate to give Compound228c (0.54 g).

Step (iii): Preparation of(3R)-2-methyl-3-[(2-nitro-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]butan-2-ol(Compound 228d)

Compound 228d (490 mg) was prepared according to the process of Step (i)in Example 59 by using Compound 76 (200 mg) and Compound 228c (213 mg).

Step (iv): Preparation of(3R)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol(Compound 228)

Compound 228 (102 mg) was prepared according to the process of Step (ii)in Example 59 by using Compound 228d (490 mg).

¹H-NMR (CDCl₃) δ: 1.15 (3H, s), 1.33 (3H, s), 1.64 (3H, d, J=7.3 Hz),1.73 (1H, s), 4.27 (1H, q, J=7.1 Hz), 7.00 (1H, d, J=9.2 Hz), 7.03 (1H,dd, J=8.9, 2.1 Hz), 7.25 (1H, d, J=2.4 Hz), 7.78 (1H, d, J=8.5 Hz), 7.88(1H, dd, J=8.5, 2.4 Hz), 8.11 (1H, s), 8.41 (1H, d, J=2.4 Hz).

Example 229

Example 229 shown in the following table was prepared according to theprocess of Example 228 by using the appropriate starting material.

TABLE 12 Example Chemical Structure Spectrum data 229

¹H-NMR (CDCl₃) δ: 1.14 (3H, s), 1.33 (3H, s), 1.64 (3H, d, J = 7.3 Hz),1.82 (1H, s), 4.27 (1H, q, J = 7.2 Hz), 6.99 (1H, d, J = 8.7 Hz), 7.02(1H, dd, J = 8.7, 2.3 Hz), 7.25 (1H, d, J = 2.3 Hz), 7.77 (1H, d, J =8.7 Hz), 7.88 (1H, dd, J = 8.7, 2.7 Hz), 8.10 (1H, s), 8.41 (1H, s).

Example 28

2-Methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol(Compound 28) can be prepared in the following manner.

Step (i): Preparation of2-methyl-1-[(2-nitro-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]propan-2-ol(Compound 28a)

To a solution of Compound 76 (1.00 g) in NMP (16 mL) at room temperaturewas added diisopropylethylamine (2.06 g). To the mixture was added1-amino-2-methylpropan-2-ol (0.74 g), and the reaction mixture washeated to 100° C. and stirred for 4 hours. The reaction solution wascooled to room temperature, and cesium carbonate (3.11 g) and2-fluoro-5-(trifluoromethyl)pyridine (1.37 g) were added thereto. Thereaction mixture was heated to 100° C. and stirred for 3 hours. Thereaction solution was cooled to room temperature, and ethyl acetate,hexane and water were added thereto. And, the objective product wasextracted in the organic layer. The organic layer was washed with water,and dried over anhydrous sodium sulfate. The organic layer wasconcentrated under reduced pressure, and the obtained residue wasslurry-washed (eluate: hexane/ethyl acetate=9/1) to give Compound 28a(1.53 g).

Step (ii): Preparation of2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol(Compound 28)

To a solution of Compound 28a (0.50 g) in methanol (6.7 mL) were addedtrimethyl orthoformate (3.7 mL), formic acid (0.52 mL) and zinc (0.44g), and the mixture was stirred heating at 70° C. for 2 hours. Thereaction mixture was filtered through Celite, and the filtrate wasconcentrated under reduced pressure. The obtained residue was dissolvedin ethyl acetate, washed with a water solution of Rochelle salt andbrine, and dried over anhydrous sodium sulfate. The concentrated crudecrystal was purified by recrystallization from hexane/ethyl acetate(=1:5) to give Compound 28 (0.33 g).

Pharmacological Test Measurement of Na Ion Current in Voltage-DependentNa Channel Gene Expressed Cell

Nav 1.7 current was measured by automated patch clamp assay using cellsstably-expressing human SCN9A.

Cells Stably-Expressing Human SCN9A

Tetracycline-induced cells stably-expressing SCN9A were obtained fromChanTest Corporation. The cells were passaged in Ham's F-12 mediumcontaining 10% fetal bovine serum, 100 units/mL Penicillin-Streptomycin,0.01 mg/mL Blasticidin, and 0.4 mg/mL Zeocin. The day before themeasurement, the medium was replaced with Ham's F-12 medium containing 1μg/mL tetracycline, 100 μmol/L sodium butyrate, 10% fetal bovine serum,and 100 units/mL Penicillin-Streptomycin. Next day, the Na ion currentwas measured by automated patch clamp assay.

Electrophysiologic Measurement of Na Ion Current

The Na ion current was measured by automated patch clamp assay using thefollowing extracellular solution and intracellular solution.

Extracellular solution (mmol/L): NaCl 130, MgCl₂ 2, CaCl₂ 2, CdCl₂ 0.1,NiCl₂ 0.1, Tetraethylammonium-Cl 18, 4-aminopyridine 1, HEPES 10,(adjusting pH 7.4 with NaOH)Intracellular solution (mmol/L): CsF 120, EGTA 10, NaCl 15, HEPES 10,(adjusting pH 7.2 with CsOH)

The control of the stimulating pulse and the data acquisition werecarried out using EPC10 amplifier and Patch Master Software (HEKA). Datawere sampled at 10 kHz, and low-pass filtered at 3 kHz. All themeasurements were carried out at room temperature. The holding potentialwas set at a potential inactivating 50% Nav 1.7 channel (around −60 mV),and depolarizing pulse of 20 milliseconds (+10 mV) was given once. Theinhibitory rate of the test compounds was calculated based on theresults of cells whose peak current was 500 pA or more when thedepolarizing pulse was given and whose whole-cell parameter did notgreatly vary until the end of the data acquisition. The inhibitory rateof the Na ion current by the test compounds was calculated according tothe following calculating formula with the peak current value generatedby the depolarizing pulse.

Inhibitory rate of Na ion current (%)=100×[(Peak current value in theabsence of Test Compound)−(Peak current value in the presence of TestCompound)]/(Peak current value in the absence of Test Compound)

Result:

The inhibitory rate of Na ion current by each Example Compound wasevaluated. The results showed that the compounds of the presentinvention exhibit the inhibitory effect for Nav 1.7. The inhibitory rate(%) wherein the concentration of each compound is 10 μmol/L is shown inthe following table.

TABLE 13 Inhibitory Inhibitory Inhibitory Inhibitory Example rate (%)Example rate (%) Example rate (%) Example rate (%)  1 83  2 85  3 65  452  5 39  6 41  7 67  8 32  9 77  10 52  11 75  12 58  13 25  14 68  1557  16 67  17 31  18 41  19 39  20 91  21 12  22 73  23 47  24 56  25 72 26 39  27 31  28 82   29^(※) 16  30 42  31 21  32 35  33 41  34 20  3539  36 42  37 44  38 43  39 46  40 42  41 29  42 31  43 20  44 26  45 42 46 33  47 38  48 17   49^(※) 23  50 25  51 44  52 46  53 69  54 62  5537  56 45  57 47  58 48  59 49  60 52  90 15  91 24  92 16  93 42  94 73  95^(※) 66   96^(※) 32  97 83  98 25  99 12 100 10 101 43 102 59 103 10104 57 105 38 106 50 107 51 108 57 109 30 110 58 111 52 112 39 113 68114 26 115 31 116 33  117^(※) 44 118 33 119 36 120 13 121 21 122 14 12364 124 61 125 13  126^(※) 7  127^(※) 16 128 24 129 51 130 48 131 62 13265 133 60 134 50 135 29 136 70 137 38 138 34 139 35 140 24 141 53 142 55143 35 144 19 145 15 146 17 147 15 148 59 149 34 150 47 151 44 152 38153 25 154 52 155 55 156 54 157 51 158 53 159 45 160 25 161 49 162 63163 47 164 63 165 35 166 54 167 71 168 77 169 46 170 32 171 60 172 64173 80 174 66 175 16 176 73 177 54 178 34 179 61 180 33 181 45  182^(※)11  183^(※) 30 184 67 185 45 186 22 187 45 188 51 189 42 190 42 191 52192 78 193 23 194 43 195 31 196 49 197 33 198 58 199 84 200 52 201 32202 21 203 26 204 28 205 46 206 69 207 65 208 43 209 48 210 48 211 44212 55 213 41 214 42 215 84 216 53 217 60 218 53 219 40 220 52 221 45222 45 223 47 224 53 225 64 226 45 227 11  228^(※) 66 229 32 * Theresults of inhibitory rate in Examples 29, 49, 95, 96, 117, 126, 127,182, 183, and 228 show inhibitory rate (%) wherein the concentration ofeach compound is 100 μmol/L.

Test (2) Evaluation of Analgesic Effect in Streptozotocin-InducedDiabetic Peripheral Neuropathy Models

Using some typical compounds among the compounds of the presentinvention, the inhibitory effect for neuropathic pain was determinedthrough the evaluation of analgesic effect in rats streptozotocin(STZ)-induced diabetic peripheral neuropathy model.

The disease animal model was prepared by means of a partially-modifiedmethod of Fox et al. (Pain 81, 307-316, 1999). STZ was intraperitoneallyadministered to 9-week old male Wistar rats in 45 mg/kg of body weightto prepare animal model suffering from diabetic peripheral neuropathy.The analgesic effect was evaluated by von Frey test. Specifically,mechanical sensitivity was measured by applying hairs (von Frey hair) tothe plantar surface of the animal's hind paw, and then the reactionthresholds (50% paw withdrawal thresholds) for the mechanicalstimulation was determined by using a formula based on Chaplan et al.(Journal of Neuroscience Methods 53, 55-63, 1994).

It was already confirmed in a preliminary study that the reactionthresholds of the animal's hind paw markedly decreased on the 21st dayor later after administering STZ, hence the evaluation of the analgesiceffect using the test compounds was done on any one day between the 21stday and the 30th day after administering STZ. One and two days beforeevaluating the test compounds, the reaction thresholds were measured toobtain an average thereof, and the average value was used as a referencevalue obtained before the test compounds would be administered.

In order to reduce the variations of the averaged values among the testgroups and the measured values in each group, the animals were dividedinto 4 to 5 groups.

In the evaluation test of the test compounds, the reaction thresholdswere measured after administering each test compound. One hour beforemeasuring the reaction thresholds, each test compound was administeredin 3 mg/kg of body weight. The strength of analgesic effect of each testcompound is expressed as the extension width (g) of reaction thresholdswhich is obtained by the calculation formula of (reaction thresholdobtained after administering test compound)−(reaction threshold obtainedbefore administering test compound).

Result:

As shown in the following table, the extension widths of reactionthresholds in each compound of the present invention were 1.3 to 6.5 g.Each number in [ ] shows extension widths in the solvent-administrationgroups for each test.

TABLE 14 Example extension width (g) 1 2.8 [1.8] 20 2.9 [0.9] 28 6 [1.9]59 5.1 [0.9] 94 4.9 [0.7] 101 1.4 [0] 118 3.4 [0.4] 123 1.3 [0] 148 3.7[0.4] 179 6.5 [1.4] 181 2.5 [1.4] 205 1.6 [0.6] 229 3.9 [0.6]

The above result indicated that the compounds of the present inventionexhibit good analgesic effects when the compounds are orallyadministered to rat models of diabetic peripheral neuropathy.

INDUSTRIAL APPLICABILITY

The compounds of the present invention can be used as a usefulmedicament for treating a disease involving Nav 1.7, for example,neuropathic pain, nociceptive pain, inflammatory pain, small-fiberneuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria,and multiple sclerosis. Thus, The compounds of the present invention canbe very useful pharmaceuticals.

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein R^(1a), R^(1b),R^(1c), and R^(1d) are each independently hydrogen, halogen, cyano, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkoxy,C₃₋₇ cycloalkylamino, C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-memberedheteroaryl, or 5- to 12-membered heteroaryloxy; wherein each alkylmoiety of the alkyl, alkoxy and alkylamino of R^(1a), R^(1b), R^(1c),and R^(1d) is optionally substituted with 1 to 5 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group B, C₃₋₇ cycloalkoxy optionally-substituted with 1to 3 substituents independently selected from Substituent-group B, and3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1to 3 substituents independently selected from Substituent-group B; eachcycloalkyl moiety of the cycloalkyl, the cycloalkoxy, and thecycloalkylamino of R^(1a), R^(1b), R^(1c), and R^(1d) is optionallysubstituted with 1 to 5 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₄ alkyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA, C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB); and each aryl moiety of the aryl and the aryloxy and each heteroarylmoiety of the heteroaryl and the heteroaryloxy of R^(1a), R^(1b),R^(1c), and R^(1d) is optionally substituted with 1 to 5 substituentsindependently selected from the group consisting of halogen, cyano, C₁₋₄alkyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group A, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, C₃₋₇ cycloalkyl optionally-substituted with 1to 3 substituents selected independently from Substituent-group B, C₃₋₇cycloalkoxy optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, 3- to 7-membered non-aromaticheterocyclyl optionally-substituted with 1 to 3 substituents selectedindependently from Substituent-group B, C₁₋₄ alkylthiooptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group A, and C₁₋₄ alkylsulfonyl optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupA; provided that at least one of R^(1a), R^(1b), R^(1c) and R^(1d) isC₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl or 5- to12-membered heteroaryloxy; R² and R³ are each independently hydrogen,C₁₋₆ alkyl which is optionally substituted with 1 to 5 substituentsindependently selected from the group consisting of cyano, halogen,hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituentsselected independently from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents selected independentlyfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents selected independently from Substituent-groupB, or C₃₋₁₀ cycloalkyl; R⁴ is hydrogen, C₁₋₆ alkyl which is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group A, C₃₋₇ cycloalkyl optionally-substituted with 1to 3 substituents independently selected from Substituent-group B, C₃₋₇cycloalkoxy optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group B, and 3- to 7-memberednon-aromatic heterocyclyl optionally-substituted with 1 to 3substituents independently selected from Substituent-group B, or C₃₋₇cycloalkyl which optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₄ alkyl optionally-substituted with 1 to 3 substituents independentlyselected from Substituent-group A, C₁₋₄ alkoxy optionally-substitutedwith 1 to 3 substituents independently selected from Substituent-groupA, C₃₋₇ cycloalkyl optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group B, and C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group B; m is 1, 2 or 3; L is CR⁷R⁸, provided that whenm is 2 or 3, each CR⁷R⁸ are independently the same or different; R⁷ andR⁸ are each independently hydrogen, hydroxyl, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₃₋₇ cycloalkyl, or C₃₋₇ cycloalkoxy, wherein each alkyl moiety of thealkyl and the alkoxy of R⁷ and R⁸ is optionally substituted with 1 to 3substituents independently selected from the group consisting ofhalogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents independently selected from Substituent-group A, C₃₋₇cycloalkyl optionally-substituted with 1 to 3 substituents independentlyselected from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group B; wherein each cycloalkyl moiety of thecycloalkyl and the cycloalkoxy of R⁷ and R⁸ is optionally substitutedwith 1 to 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₄ alkyl optionally-substituted with1 to 3 substituents independently selected from Substituent-group A,C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group B, and C₃₋₇ cycloalkoxy optionally-substitutedwith 1 to 3 substituents independently selected from Substituent-groupB; or R² and R³ may be combined together with the carbon atom to whichthey are attached to form the following group of formula (II) with —OR⁴:

wherein: e and f are each independently 1, 2 or 3; V is single bond oroxygen atom; R^(5a), R^(5b), R^(5c), and R^(5d) are each independentlyhydrogen, halogen, hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy; wherein eachalkyl moiety of the alkyl and the alkoxy of R^(5a), R^(5b), R^(5c), andR^(5d) is optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of halogen, hydroxyl, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group A, C₃₋₇ cycloalkyl optionally-substituted with 1to 3 substituents independently selected from Substituent-group B, C₃₋₇cycloalkoxy optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group B, and 3- to 7-memberednon-aromatic heterocyclyl optionally-substituted with 1 to 3substituents independently selected from Substituent-group B; or in R²,R³, —OR⁴ and CR⁷R⁸ of L, R² and R⁷ may be combined together with thecarbon atom to which they are attached to form the following group offormula (IV) with R³, —OR⁴ and R⁸:

wherein: m¹ is 0 or 1; and m² is 0 or 1 and j is 1, 2, 3 or 4 when m¹ is1; or m² is 0, 1 or 2 and j is 1, 2, 3 or 4 when m¹ is 0; R^(9a),R^(9b), R^(9c), and R^(9d) are each independently hydrogen, halogen,hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy; wherein each alkyl moiety of thealkyl and the alkoxy of R^(9a), R^(9b), R^(9c), and R^(9d) is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halogen, hydroxyl, C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group A, C₃₋₇ cycloalkyl optionally-substituted with 1to 3 substituents independently selected from Substituent-group B, C₃₋₇cycloalkoxy optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group B, and 3- to 7-memberednon-aromatic heterocyclyl optionally-substituted with 1 to 3substituents independently selected from Substituent-group B; or R³ and—OR⁴ may be combined together with the carbon atom to which they areattached to form the following group of formula (III) with R²:

wherein: h is 1, 2, 3, or 4; and R^(6a), R^(6b), and R^(6c) are eachindependently hydrogen, halogen, hydroxyl, C₁₋₄ alkyl, or C₁₋₄ alkoxy;wherein each alkyl moiety of the alkyl and the alkoxy of R^(6a), R^(6b),and R^(6c) is optionally substituted with 1 to 3 substituentsindependently selected from the group consisting of halogen, hydroxyl,C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group A, C₃₋₇ cycloalkyloptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group B, C₃₋₇ cycloalkoxy optionally-substituted with 1to 3 substituents independently selected from Substituent-group B, and3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1to 3 substituents independently selected from Substituent-group B;provided that all of R², R³ and —OR⁴ are not combined together to form aring; each Substituent-group A is independently halogen, hydroxyl, C₁₋₄alkoxy, C₃₋₇ cycloalkyl, or C₃₋₇ cycloalkoxy; and each Substituent-groupB is independently halogen, hydroxyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₇cycloalkyl, or C₃₋₇ cycloalkoxy; provided that the following compoundsare excluded from the compounds of Formula (I):6-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-1-(2-methoxyethyl)-1H-benzimidazole,2-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-1-yl]ethanol,2-{5-[5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl]-1H-benzimidazol-1-yl}ethanol,2-{5-[3-(2-methoxyethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol,2-{5-[3-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol,2-butyl-6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-2-(3-methylbutyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,2-{5-[1-(2-hydroxyethyl)-1H-benzimidazol-5-yl]-1H-1,2,4-triazol-1-yl}ethanol,6-(2-chlorophenyl)-1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile,2-chloro-6-{7-fluoro-1-[(1S,3S)-3-methoxycyclohexyl]-1H-benzimidazol-5-yl}-9-(tetrahydro-2H-pyran-2-yl)-9H-purine,and2-{5-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]-1H-benzimidazol-1-yl}ethanol.2. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein: R^(1a), R^(1b), R^(1c), and R^(1d) are eachindependently hydrogen, halogen, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₆₋₁₀aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-memberedheteroaryloxy; wherein each alkyl moiety of the alkyl and the alkoxy ofR^(1a), R^(1b), R^(1c), and R^(1d) is optionally substituted with 1 to 3independently selected halogens; wherein each aryl moiety of the aryland the aryloxy and each heteroaryl moiety of the heteroaryl and theheteroaryloxy of R^(1a), R^(1b), R^(1c), and R^(1d) is optionallysubstituted with 1 to 3 substituents independently selected from thegroup consisting of halogen, cyano, C₁₋₄ alkyl optionally-substitutedwith 1 to 3 substituents independently selected from Substituent-groupA, C₁₋₄ alkoxy optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group A, and C₁₋₄ alkylsulfonyloptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group A.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R^(1a), R^(1b),R^(1c), and R^(1d) are each independently hydrogen, C₆₋₁₀ aryl, C₆₋₁₀aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-memberedheteroaryloxy, wherein each aryl moiety of the aryl and the aryloxy andeach heteroaryl moiety of the heteroaryl and the heteroaryloxy ofR^(1a), R^(1b), R^(1c), and R^(1d) is optionally substituted with 1 to 3substituents independently selected from the group consisting of halogenand C₁₋₄ alkyl optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group A.
 4. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R^(1a)and R^(1d) are each hydrogen.
 5. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R² and R³ are eachindependently hydrogen or C₁₋₆ alkyl which may be independentlysubstituted with 1 to 5 substituents independently selected from thegroup consisting of cyano, halogen, hydroxyl, and C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group A, provided that both of R² and R³ are nothydrogen; or R² and R³ may be combined together with the carbon atom towhich they are attached to form the following group of formula (IIa)with —OR⁴:

wherein: e and f are each independently 1 or 2; R^(5a), R^(5b), R^(5c),and R^(5d) are each independently hydrogen or halogen; or in R², R³,—OR⁴ and CR⁷R⁸ in L: R² and R⁷ may be combined together with the carbonatom to which they are attached to form the following group of formula(IVa) with R³, —OR⁴, and R⁸:

wherein m¹ is 0; m² is 1 or 2; j is 1, 2 or 3; R³ is hydrogen or C₁₋₆alkyl which may be independently substituted with 1 to 5 substituentsindependently selected from the group consisting of cyano, halogen,hydroxyl, and C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents independently selected from Substituent-group A; andR^(9a), R^(9b), R^(9c), and R^(9d) are each independently hydrogen orhalogen.
 6. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein: R² and R³ are each independently C₁₋₆ alkyloptionally-substituted 1 to 5 independently selected halogens; or R² andR³ may be combined together with the carbon atom to which they areattached to form the following group of formula (IIb) with —OR⁴:

wherein: e and f are each independently 1 or 2; and R^(5a), R^(5b),R^(5c), and R^(5d) are each independently hydrogen or halogen; or in R²,R³, —OR⁴ and CR⁷R⁸ in L: R² and R⁷ may be combined together with thecarbon atom to which they are attached to form the following group offormula (IVa) with R³, —OR⁴ and R⁸:

wherein: m¹ is 0; m² is 1 or 2; j is 1, 2 or 3; R⁴ is hydrogen; andR^(9a), R^(9b), R^(9c), and R^(9d) are each independently hydrogen orhalogen.
 7. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein: R² and R³ are each independently hydrogen or C₁₋₆alkyl optionally-substituted with 1 to 5 independently selectedhalogens.
 8. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein: R⁴ is hydrogen, C₁₋₄ alkyl optionally-substitutedwith 1 to 3 independently selected halogens, or C₃₋₇ cycloalkyl which isoptionally substituted with 1 to 3 substituents independently selectedfrom the group consisting of halogen, hydroxyl, and C₁₋₄ alkoxyoptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group A; or R³ and —OR⁴ may be combined together withthe carbon atom to which they are attached to form the following groupof formula (IIIa) with R²:

wherein: h is 1, 2, or 3; R^(6a), R^(6b), and R^(6c) are eachindependently hydrogen, halogen, or C₁₋₄ alkyl optionally-substitutedwith 1 to 3 independently selected halogens.
 9. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein: R⁴ is hydrogen,C₁₋₄ alkyl optionally-substituted with 1 to 3 independently selectedhalogens, or C₃₋₇ cycloalkyl which is optionally substituted with 1 to 3substituents independently selected from the group consisting ofhalogen, hydroxyl, and C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents independently selected from Substituent-group A.
 10. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁴ is hydrogen.
 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R⁷ and R⁸ are eachindependently hydrogen or C₁₋₄ alkyl which is optionally substitutedwith 1 to 3 substituents independently selected from the groupconsisting of halogen, hydroxyl, C₁₋₄ alkoxy optionally-substituted with1 to 3 substituents independently selected from Substituent-group A,C₃₋₇ cycloalkyl optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group B, C₃₋₇ cycloalkoxyoptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyloptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group B, and m is 1 or
 2. 12. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R⁷ and R⁸ areeach hydrogen, and m is
 1. 13. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R^(1b) or R^(1c) isC₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl, or 5- to12-membered heteroaryloxy; wherein each aryl moiety of the aryl and thearyloxy and each heteroaryl moiety of the heteroaryl and theheteroaryloxy of R^(1b) and R^(1c) is optionally substituted with 1 to 3substituents independently selected from the group consisting ofhalogen, cyano, C₁₋₄ alkyl optionally-substituted with 1 to 3substituents independently selected from Substituent-group A, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents independentlyselected from Substituent-group A, and C₁₋₄ alkylsulfonyloptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group A.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R^(1b) is C₆₋₁₀ aryl,C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-memberedheteroaryloxy; wherein each aryl moiety of the aryl and the aryloxy andeach heteroaryl moiety of the heteroaryl and the heteroaryloxy of R^(1b)is optionally substituted with 1 to 3 substituents independentlyselected from the group consisting of halogen, cyano, C₁₋₄ alkyloptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group A, C₁₋₄ alkoxy optionally-substituted with 1 to 3substituents independently selected from Substituent-group A, and C₁₋₄alkylsulfonyl optionally-substituted with 1 to 3 substituentsindependently selected from Substituent-group A.
 15. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein: R^(1c)is C₆₋₁₀ aryl, C₆₋₁₀ aryloxy, 5- to 12-membered heteroaryl, or 5- to12-membered heteroaryloxy; wherein each aryl moiety of the aryl and thearyloxy and each heteroaryl moiety of the heteroaryl and theheteroaryloxy of R^(1c) is optionally substituted with 1 to 3substituents independently selected from the group consisting ofhalogen, cyano, C₁₋₄ alkyl optionally-substituted with 1 to 3substituents independently selected from Substituent-group A, C₁₋₄alkoxy optionally-substituted with 1 to 3 substituents independentlyselected from Substituent-group A, and C₁₋₄ alkylsulfonyloptionally-substituted with 1 to 3 substituents independently selectedfrom Substituent-group A.
 16. The compound of claim 1, or apharmaceutically acceptable salt thereof, which is selected from thegroup of compounds consisting of:1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,6-(4-fluorophenoxy)-1-(tetrahydrofuran-2-ylmethyl)-1H-benzimidazole,1-(tetrahydrofuran-2-ylmethyl)-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,1-[2-(cyclopentyloxy)ethyl]-6-[4-(trifluoromethyl)phenyl]-1H-benzimidazole,2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,1-[2-(cyclopentyloxy)ethyl]-6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazole,2-methyl-1-[6-(4-methylphenoxy)-1H-benzimidazol-1-yl]propan-2-ol,2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,2-methyl-1-(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,2-methyl-1-(5-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,1-{5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,3-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]oxetan-3-ol,1-[(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)methyl]cyclobutanol,2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol,2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,3-({6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol,3-{[6-(2-chloro-4-fluorophenoxy)-1H-benzimidazol-1-yl]methyl}oxetan-3-ol,cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol,1-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,1-[6-(4-chloro-2-fluorophenyl)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,4-{6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylbutan-2-ol,1-{5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,2-methyl-1-{5-[4-(trifluoromethoxy)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,1-{5-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,and(3S)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol.17. The compound of claim 1, or a pharmaceutically acceptable saltthereof, which is selected from the group of compounds consisting of:1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,2-methyl-1-{6-[4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}propan-2-ol,2-methyl-1-{6-[5-(trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan-2-ol,2-methyl-1-{6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,1-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol,2-methyl-1-{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol,2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]-1H-benzimidazol-1-yl}propan-2-ol,2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,2-methyl-1-(5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2-methylpropan-2-ol,2-methyl-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol,2-methyl-1-(6-{[5-(2,2,2-trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol,3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol,cis-4-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol,1-{6-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2-methylpropan-2-ol,3-({6-[2-methoxy-4-(trifluoromethyl)phenyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol,and(3S)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol.18. A pharmaceutical composition comprising the compound of claim 1, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable additive agent.
 19. A method of treating a disease involvingNAV1.7 (SCN9A) in a subject, comprising administering to the subject thecompound of claim 1, or a pharmaceutically acceptable salt thereof, asan active ingredient.
 20. (canceled)
 21. A pharmaceutical combinationcomprising the compound of claim 1, or a pharmaceutically acceptablesalt thereof, and at least one drug selected from the group consistingof an antiepileptic agent, an antidepressive agent, a narcoticanalgesic, an anti-inflammatory agent, a reductase inhibitor, and aprostaglandin derivative drug.
 22. (canceled)
 23. A method of treatingneuropathic pain, nociceptive pain, inflammatory pain, small-fiberneuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria,or multiple sclerosis in a mammal in need thereof, which comprisesadministering a therapeutically effective amount of the compound ofclaim 1, or a pharmaceutically acceptable salt thereof, to the mammal.